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Hypoglycemia in the Toddler and Child
Introduction
Glucose is an obligate fuel for the brain under physiological conditions. The brain can neither synthesize glucose nor store more than approximately a 20-minute supply of glycogen; therefore brain survival requires a continuous supply of glucose. The brain can use alternative fuels from the circulation, provided their concentrations rise high enough to enter the brain in sufficient amounts; for example, elevated ketones during prolonged fasting or lactate during vigorous exercise and in untreated type 1 glycogen storage disease (GSD). Blood-to-brain glucose transport mediated by glucose transporter 1 (GLUT-1) is a direct function of the arterial plasma glucose concentration, and physiologic mechanisms normally maintain plasma glucose at levels that ensure adequate glucose delivery to the brain. At physiological (70–100 mg/dL ) plasma glucose concentrations, the rate of blood-to-brain glucose transport exceeds the rate of brain glucose metabolism. At plasma glucose concentrations lower than 54 mg/dL, however, the cerebral metabolic rate of glucose decreases; and at even lower plasma glucose concentrations, functional brain failure occurs, and profound and prolonged hypoglycemia causes permanent brain injury and eventually brain death.
Beyond the newborn period and early infancy, hypoglycemia is uncommon and is usually caused by an acquired disorder of the endocrine system, prolonged fasting in susceptible individuals (e.g., an intercurrent gastrointestinal illness), congenital abnormalities, such as hyperinsulinism (HI) or inborn errors of metabolism, or accidental and rarely deliberate exposure to medication or toxins. As the interval between feedings increases in the growing infant, physiologic endocrine and metabolic processes normally ensure the maintenance of normoglycemia; however, hypoglycemia can first manifest later in infancy or early childhood when there are mild congenital defects of these systems. In contrast, hypoglycemia presenting in older children and adults is typically caused by an acquired disorder.
This chapter describes an approach to diagnosis based on identifying the specific cause of failure to maintain normal glucose homeostasis. Key diagnostic information is often best derived from blood and urine specimens (referred to as critical samples ) obtained at the time of hypoglycemia and immediately before reversing hypoglycemia.
Physiologic development of glucose metabolism during infancy and childhood
Glucose Production and Utilization
Rates of glucose flux into and out of the circulation are normally tightly regulated and systemic glucose balance is maintained, while ensuring a continuous supply of glucose to the brain. After a typical carbohydrate-containing meal, increased insulin secretion (together with inhibition of counterregulatory hormone secretion) leads to rapid disposal of ingested glucose, either for immediate energy needs or storage via deposition of glycogen and conversion to fat, resulting in restoration of plasma glucose concentrations to basal levels within 2 to 3 hours. Bier et al. showed that in children, ranging from premature infants to age 6 years, mean glucose production rates are 5 to 8 mg/kg/min; thereafter, glucose production as a function of body weight decreases toward the mean adult value of 2.3 mg/kg/min. Furthermore, the rate of glucose production is linearly correlated with estimated brain weight at all ages. Because the brain accounts for the bulk of daily glucose utilization, it is not surprising that adult glucose production rates are reached by mid-childhood (body weight ~ 30 kg), when the child’s brain weighs about 90% of the adult brain ( Fig. 23.1 ).
During fasting, the brain initially uses glucose almost exclusively provided from a combination of glycogenolysis and gluconeogenesis in the liver. As liver glycogen stores diminish, adipose tissue lipolysis is activated to increase availability of free fatty acids (FFA) as fuel for peripheral tissues, such as muscle, and for ketogenesis in the liver, which makes ketones available as a brain fuel and partly replaces glucose utilization. Note that the time to reach the fasting hyperketonemia stage is markedly shorter in younger infants and children than in adults, because of their larger ratio of brain relative to muscle mass. As shown in Fig. 23.2 , the change in sources of fuel for the brain is reflected in the changes in plasma concentrations of the major metabolic fuels. The substantially smaller muscle mass of infants and young children relative to brain mass limits their ability to tolerate prolonged fasting. Because brain growth is nearly complete by 10 to 12 years of age, plasma glucose can be maintained above 70 mg/dL for progressively longer fasting durations in adolescents and adults. Nonetheless, most full-term infants, from about 1 week to 1 year of age, are able to tolerate fasting for 15 to 18 hours before plasma glucose decreases below 70 mg/dL, and by 1 year of age, most normal children are able to fast for up to 24 hours. By 5 years of age, a fast of up to 36 hours may be tolerated, and most adults can maintain fasting plasma glucose above 70 mg/dL for 48 to 72 hours ( Fig. 23.3 ). When hypoglycemia is induced by fasting for a shorter duration than would be expected for the child’s age, the possibility of an underlying hypoglycemia disorder should be considered.
Adaptation to Longer Feeding Intervals
With feeding, plasma insulin concentrations in normal-weight children rise from basal levels of 3 to 10 μU/mL to peak levels of 20 to 50 μU/mL, which serves to stimulate hepatic glycogen synthesis, inhibit hepatic glycogenolysis and gluconeogenesis, and enhance peripheral (muscle and adipose tissue) glucose uptake and utilization ( Table 23.1 ). Simultaneously, triglyceride synthesis is activated and lipolysis and ketogenesis are suppressed. In the postabsorptive state, a characteristic sequence of physiological responses are involved in preventing or correcting hypoglycemia. The earliest response to decreasing plasma glucose concentrations is a decrease in insulin secretion, as plasma glucose declines within the physiological range (80–85 mg/dL) followed by increased secretion of glucose counterregulatory hormones (glucagon, epinephrine, cortisol, and growth hormone [GH]), when plasma glucose falls just below the postabsorptive physiological range (65–70 mg/dL), and sympathetic neural activation occurs at 55 mg/dL ( Fig. 23.4 ). The combined effects of suppressed insulin secretion, increased levels of counterregulatory hormones, and sympathetic neural activation mobilize stored fuels and reduce glucose utilization, thereby preventing hypoglycemia. With insulin levels suppressed, elevated glucagon secretion and sympathetic neural activation trigger glycogenolysis, the first phase in the metabolic defense against hypoglycemia. In infants, liver glycogen stores may provide glucose for up to 4 hours (see Fig. 23.3 ). As the child grows, hepatic glycogen content relative to brain glucose utilization is greater and may be able to provide glucose for up to 8 hours of fasting. Isolated glucagon deficiency is extremely rare and, with the exception of children on beta-blocker drugs, deficiency of sympathetic nervous activity is equally unusual. Therefore hypoglycemia occurring within 2 to 4 hours of a feed suggests either a primary disorder of glycogenolysis or excess (dysregulated) insulin secretion. As glycogen stores become depleted, maintenance of plasma glucose levels relies on gluconeogenesis and reduced tissue glucose utilization (resulting from increased oxidation of FFA and ketones) (see Fig. 23.3 ). The main gluconeogenic precursors are amino acids, especially alanine and glutamine, from skeletal muscle, and glycerol from adipose tissue lipolysis ( Fig. 23.5 ). FFA become the body’s major fuel source, as the duration of fasting becomes more prolonged. Mitochondrial fatty acid oxidation in the liver produces ketone bodies (acetoacetate and β-hydroxybutyrate [BOHB]), which are used for energy production by the brain and skeletal muscle, including cardiac muscle (see Fig. 23.2 ). Oxidation of FFA and ketone utilization decreases peripheral glucose utilization, which helps to ensure an adequate supply of glucose to the brain and tissues that can only use glucose as fuel (e.g., red blood cells and renal medullae), while preventing excessive breakdown of muscle protein. Lipolysis of triglycerides in adipose tissue is triggered by low levels of insulin together with increased secretion of the counterregulatory hormones (especially GH ) and sympathetic neural activation. In infants, elevation of plasma ketone concentrations begins within 12 to 18 hours of fasting; whereas, in older children, substantial ketonemia may not appear until 18 to 24 hours of fasting. Cortisol, secreted in response to stress, accelerates gluconeogenesis and lipolysis and decreases glucose utilization.
Table 23.1
Hormonal Regulation of Fuel Metabolism
| Insulin | Glucagon | Epinephrine a | Cortisol | Growth hormone | |
|---|---|---|---|---|---|
| Glucose uptake | + | - | - | - | |
| Glycogenolysis | – | + | + | b | b |
| Gluconeogenesis | – | + | + | + | + |
| Lipolysis | – | + | + | + | |
| Ketogenesis | – | + | + | + |
+ denotes stimulates, – inhibits;
a includes sympathetic nervous system activation
b cortisol stimulates glycogen synthesis, and both cortisol and growth hormone exert permissive effects on the gluconeogenic and glycogenolytic effects of glucagon and epinephrine.
Defects in gluconeogenesis (e.g., fructose-1,6-bisphosphatase deficiency; see Fig. 23.5 ) usually become manifest only after glycogen stores have been depleted; accordingly, hypoglycemia typically does not occur in the recently fed state. Disorders of fatty acid oxidation also typically manifest after more prolonged fasting. In the first few months of life, the interval between feedings in the on-demand breastfed infant gradually increase from about 2 to 3 hours to 4 hours or more, and eventually to 8 to 12 hours as nighttime feedings are omitted. Therefore disorders of gluconeogenesis and fatty acid oxidation seldom present as hypoglycemia in the newborn period when feeding is frequent; rather, they present later in infancy as the interval between feeds becomes more prolonged. They may, however, present immediately after birth before lactation is established. Congenital or acquired deficiencies of cortisol and GH may also cause hypoglycemia either in the newborn period, if congenital and severe, or later in infancy when longer periods of fasting typically occur. Combined deficiency of cortisol (adrenocorticotropic hormone [ACTH]) and GH in hypopituitarism may cause earlier onset and more severe hypoglycemia than occurs with isolated deficiencies of either GH or cortisol.
Symptoms, signs, and effects of hypoglycemia
Control of the counterregulatory responses is at least partially local: a low glucose concentration and a decrease in intraislet β-cell insulin secretion stimulate glucagon secretion. Low plasma glucose concentrations are sensed in the hepatic portal vein, as well as in the gut, carotid body, and oral cavity (and are transmitted to the brain) and also are directly sensed in the hindbrain and hypothalamus, which initiates an increase in sympathoadrenal activity.
The trigger for counterregulatory responses is the plasma glucose level itself. The rate at which glucose decreases and the absolute level of insulin have little effect. The symptoms of hypoglycemia, which reflect the brain’s response to glucose deprivation, have been extensively studied and well characterized in adults ( Box 23.1 ). Autonomic (neurogenic) symptoms primarily arise from perception of the physiological changes caused by sympathetic (not adrenomedullary) neural activation and include both adrenergic (tremor, palpitations, anxiety/nervousness) and cholinergic responses (sweating, hunger, paresthesias). Awareness of hypoglycemia chiefly depends on perception of the central and peripheral effects of these neurogenic (in contrast to neuroglycopenic) responses to hypoglycemia. Neurogenic symptoms are perceived at a plasma glucose of less than 54 mg/dL, the threshold at which brain glucose utilization becomes limiting. In older children and adults, the search for food or assistance is a crucially important defense against more severe hypoglycemia. Plasma glucose below 50 mg/dL causes neuroglycopenic manifestations (the result of an insufficient supply of glucose to maintain brain energy), such as impaired cognition, loss of motor coordination, confusion, coma, and seizures. Hypothermia often occurs with prolonged hypoglycemia in older children and adults and is thought to be the result of a neurogenic mechanism. It is noteworthy that young children (6–11 years old) with type 1 diabetes have poor ability to detect low blood glucose levels.
Box 23.1
Symptoms of Hypoglycemia
Neurogenic symptoms caused by activation of autonomic nervous system
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Sweating
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Shakiness, trembling
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Tachycardia
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Anxiety, nervousness
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Weakness
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Hunger
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Nausea, vomiting
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Pallor
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Hypothermia
Neuroglycopenic symptoms caused by decreased cerebral glucose use
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Headache
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Visual disturbances
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Lethargy, lassitude
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Restlessness, irritability
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Difficulty with speech and thinking, inability to concentrate
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Mental confusion
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Somnolence, stupor, prolonged sleep
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Loss of consciousness, coma
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Hypothermia
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Twitching, convulsions, “epilepsy”
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Bizarre neurologic signs
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Motor disturbances
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Sensory disturbances
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Loss of intellectual ability
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Personality changes
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Bizarre behavior
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Outburst of temper
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Psychologic disintegration
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Manic behavior
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Depression
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Psychoses
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Permanent mental or neurologic damage
Activation thresholds for the neuroendocrine responses have been best established for healthy young adults and vary only slightly by sex, age, exercise, sleep, and nutritional status. There is no evidence that the definition of hypoglycemia should be lower in infants and young children. Indeed, both epinephrine and GH are released at a higher plasma glucose level in children than in adults, suggesting that the threshold for neuroendocrine responses to decreasing plasma glucose levels in children is not lower and may actually be higher than in adults. At comparable plasma glucose thresholds, epinephrine levels are also markedly increased in children as compared with adults. Drugs alter the neuroendocrine responses to hypoglycemia, for example, beta-blockers, dampen the response, whereas caffeine amplifies the response. Prior exposure to hypoglycemia and hyperglycemia cause clinically important alterations of neuroendocrine response thresholds. Even a single episode of moderately severe hypoglycemia can blunt or lower the activation threshold for 24 hours or more; after prolonged or recurrent hypoglycemia, autonomic responses may be sufficiently attenuated that neuroglycopenic effects may be the sole clinical manifestation of severe hypoglycemia, a condition referred to as hypoglycemia-associated autonomic failure ( HAAF ). HAAF has been demonstrated in adults and children with type 1 diabetes, in nondiabetic adults with an insulinoma, and in infants with recurrent hypoglycemia caused by congenital HI. Conversely, chronic hyperglycemia is associated with higher glucose thresholds for counterregulatory responses.
The effects on cognition, behavior, and level of consciousness are typically completely reversed when the glucose level is raised, although subtle neuropsychological impairment may be measurable days later. Severe and prolonged neuroglycopenia, however, causes brain injury and neuronal death. In experiments with primates, plasma glucose below 20 mg/dL for 5 to 6 hours reliably produces severe injury. In both infants and adults, magnetic resonance imaging (MRI) shows characteristic changes caused by hypoglycemia-induced brain injury. Pathologic changes are observed particularly in cortical tissue and white matter; whereas, the cerebellum and brainstem tend to be spared. Permanent cognitive impairment is common both in children and adults after recurrent, severe hypoglycemia.
Definition of hypoglycemia
Clinical hypoglycemia is defined as a plasma glucose concentration low enough to elicit defensive neuroendocrine responses, which cause symptoms and/or signs, or impair brain function. Because the signs and symptoms are nonspecific, hypoglycemia may be difficult to recognize, and a single low plasma glucose concentration may be an artifact. For example, when blood is drawn but plasma not immediately separated from the cellular elements, glycolysis in red cells causes glucose levels to decline at a rate of 6 mg/dL/h. This is a common cause of artifactually low glucose levels reported in metabolic panels measured at commercial laboratories. Point-of-care glucose meters, originally designed for diabetes management, are useful for screening purposes, but their accuracy is limited to approximately ± 10 to 15 mg/dL in the hypoglycemia range. Whole blood glucose levels are approximately 15% lower than plasma concentrations, and it is preferable consistently to refer to plasma glucose concentrations. Before establishing a diagnosis of hypoglycemia and undertaking a diagnostic evaluation, it is essential to confirm a low plasma glucose concentration using a clinical laboratory method. For these reasons, guidelines emphasize the value of Whipple’s triad for confirming hypoglycemia : (1) symptoms and/or signs consistent with hypoglycemia, (2) a documented low plasma glucose concentration, and (3) relief of symptoms and signs when plasma glucose is restored to normal. Because infants and young children cannot dependably recognize or communicate their symptoms, recognition of hypoglycemia may require confirmation by repeated measurements of plasma glucose concentration and formal provocative testing.
It is important to appreciate that hypoglycemia cannot be defined as a single specific plasma glucose concentration because thresholds for specific brain responses to hypoglycemia occur across a range of plasma glucose concentrations, and these thresholds can be altered by the presence of alternative fuels, such as ketones, and also by recent antecedent hypoglycemia. It is also not possible to identify a single plasma glucose value that causes brain injury, and the extent of injury is influenced by other factors, such as the duration and degree of hypoglycemia, availability of alternative fuels, and potential artifacts and technical factors that lead to inaccuracies in glucose measurements.
Despite the frequency with which hypoglycemia is not accompanied by obvious symptoms in infants, evidence of injury to the brain from prolonged or recurrent hypoglycemia suggests the same clinical thresholds and treatment goals are applicable irrespective of age beyond the immediate (48–72 hours) newborn period. Two different hypoglycemia thresholds are recommended for use in clinical practice. To determine the etiology of hypoglycemia and terminate a diagnostic provocative fasting test, obtain critical samples when plasma glucose is less than 55 mg/dL. For therapeutic purposes, however, the lower limit of the plasma glucose range should be 70 mg/dL (see Fig. 23.4 ). This goal is important to avoid periods of low glucose that may blunt the neuroendocrine and symptomatic responses to hypoglycemia and lead to greater susceptibility to subsequent more severe episodes of hypoglycemia.
As noted earlier, the effects of specific plasma glucose levels on the central nervous system may vary among patients, especially after experiencing previous episodes of hypoglycemia. Because there is no exact correspondence between the risk of harm (including brain injury) and either severity of symptoms or specific plasma glucose levels, hypoglycemia should always be treated urgently.
Fasting systems approach to the diagnosis of hypoglycemia
To provide appropriate treatment for a hypoglycemia disorder, it is essential to establish a specific diagnosis of the etiology. Because most hypoglycemia disorders, especially in infants and children, involve a disturbance of fasting adaptation, the best approach to diagnosis is a closely monitored fasting test, which both reproduces the hypoglycemia and surveys the integrity of the major metabolic and endocrine systems shown in Figs. 23.3 and 23.5 and in Table 23.1 . These “fasting systems” include the four metabolic systems (hepatic glycogenolysis, hepatic gluconeogenesis, adipose tissue lipolysis, and hepatic ketogenesis) and their regulation by the endocrine system. The endocrine system includes: (1) insulin, which suppresses activity of all four metabolic systems; and (2) the four counterregulatory hormones that oppose insulin action in specific tissues: (a) glucagon acts acutely on liver to stimulate glycogenolysis and gluconeogenesis and facilitate ketogenesis; (b) adrenergic nervous system activation (reflected by increases in plasma epinephrine levels) acts acutely on adipose tissue and liver to stimulate lipolysis, ketogenesis, glycogenolysis, and gluconeogenesis; (c) cortisol has longer term effects required for maintaining liver glycogen stores and promoting gluconeogenesis; and (d) GH, which has longer-term effects on the capacity for adipose tissue lipolysis (see Table 23.1 ).
The operation of these metabolic and endocrine systems is reflected by changes in major circulating metabolic fuels during normal fasting, as shown in Fig. 23.2 . As liver glycogen reserves become depleted, plasma glucose falls toward hypoglycemic levels, plasma lactate declines by 25% to 50% (a marker of enhanced gluconeogenesis), plasma FFA rise 4- to 6-fold (a marker of lipolysis), and plasma ketones rise 20- to 40-fold (a marker of ketogenesis, usually measured as BOHB the major ketone). Measurement of these fuels at the time of hypoglycemia (the critical samples) provides crucial information about which component of the fasting systems is responsible for causing hypoglycemia ( Fig. 23.6 ). For example, abnormal elevation of plasma lactate suggests a defect in gluconeogenesis; abnormal suppression of BOHB, with a normal or excessive rise in FFA, suggests a defect in fatty acid oxidation; abnormal suppression of both FFA and BOHB suggests excessive insulin action; and a normal fall in plasma lactate accompanied by a rapid rise in FFA and ketone concentrations occurring after a relatively brief period of fasting (i.e., ketotic hypoglycemia) suggests a defect in glycogenolysis. Cortisol or GH deficiency usually manifest with ketotic hypoglycemia; however, in the neonatal period, combined pituitary hormone deficiencies, especially, may present as hypoketotic hypoglycemia, mimicking HI. Deficiency of sympathetic nervous activity (e.g., secondary to beta-blocker drugs) may present with hypoketotic hypoglycemia because of impaired lipolysis. Deficiency of glucagon as a primary disease has not been described, whereas secondary deficiency is common in patients with recurrent hypoglycemia, such as congenital HI or type 1 diabetes (HAAF).
Additional tests may be done separately to further assess for specific disorders or can be conveniently added at the end of the fasting test by using extra blood obtained with the critical sample. Serum insulin levels are often not elevated enough for diagnosis of HI disorders; therefore insulin levels, within the normal range, do not exclude the possibility of HI; plasma C-peptide levels may more accurately reflect pancreatic insulin secretion because insulin delivered by the portal vein is variably extracted by the liver, whereas C-peptide passes through the liver without hepatic extraction. HI can be conveniently confirmed with a glucagon stimulation test: in normal children, there is little or no response at the time of hypoglycemia, because liver glycogen stores have been depleted; whereas in HI, there is an abnormally large glycemic response caused by inhibition of glycogenolysis. Plasma levels of cortisol or GH sometimes increase to values sufficiently high during hypoglycemia to exclude deficiency of either or both; however, before making a diagnosis of cortisol or GH deficiency, low values must be confirmed by additional specific provocative tests of these hormones. Plasma free and total carnitine levels, together with the profile of plasma acylcarnitines, are useful for the diagnosis of most, but not all, of the fatty acid oxidation defects.
Other tests may be considered if specific disorders are suspected. Plasma ammonia concentrations are elevated 3- to 5-fold in patients with the HI hyperammonemia syndrome caused by activating mutations of GLUD1 . Plasma C-peptide suppression in the face of elevated insulin levels may be helpful in demonstrating exogenous insulin administration. Plasma insulin-like growth factor binding protein-1 (IGFBP-1) concentration usually rises 5- to 10-fold as insulin levels decline during fasting, so that low IGFB-1 values support a diagnosis of HI. Specimens to test for drugs or toxins may be considered in cases of suspected ingestion of oral hypoglycemic drugs, plant toxins (unripe ackee-ackee fruit, litchi fruit), or surreptitious insulin administration (factitious hypoglycemia or Munchausen by proxy).
Detailed methods for performing fasting tests and other tests useful for diagnosis of hypoglycemia are provided at the end of this chapter.
Major causes of hypoglycemia in the toddler and child
Hyperinsulinism
HI is the most common and the most severe form of hypoglycemia in neonates and young infants, and is also one of the most common causes of hypoglycemia in toddlers and older children. Hypoglycemia caused by HI is particularly dangerous to the brain, because glucose deficiency cannot be compensated for by increased production of ketones to support brain metabolism. Although many neonates with severe congenital HI present in the first week of life, milder genetic forms of HI continue to be an important cause of hypoglycemia throughout infancy. Older children and adolescents with HI may have acquired insulin-secreting pancreatic adenomas.
Congenital HI may present beyond the first months of life as feeding intervals lengthen and overnight feedings are omitted. Such infants may have early morning lethargy or seizures and may have a history of previous seizures and unexplained developmental delay, or of hypoglycemia in the newborn period that was not fully evaluated or treated. In dominant forms of HI, there may be a history of hypoglycemic symptoms in a parent or other relatives; however, carriers may often not recognize symptoms. As outlined in Chapter 7 , all of the genetic causes of HI may initially present in the neonatal period.
The diagnosis of HI is suggested when hypoglycemia is not accompanied by hyperketonemia and can be confirmed when injection of glucagon causes a large increase (> 30–40 mg/dL relative to baseline) in plasma glucose concentration. HI may be suggested by increased rates of glucose utilization (glucose infusion rate [GIR] > 8 mg/kg/min), but this is less consistently present in older children than in neonates. A critical specimen obtained during hypoglycemia, which demonstrates increased levels of insulin or C-peptide can be conclusive; however, it is often not possible to demonstrate clearly elevated insulin levels. Table 23.2 shows the diagnostic criteria for hyperinsulinemic hypoglycemia. In cases of surreptitious insulin administration, standard insulin immunoassays may not detect exogenously injected insulin analogs, such as lispro, aspart, glargine, etc. In suspected cases, specific assays must be requested.
Table 23.2
Diagnostic Criteria for Hyperinsulinemic Hypoglycemia
(Modified from Ferrara, C., Patel, P., Becker, S., Stanley, C.A., Kelly, A. (2016). Biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children. J Pediatr, 168, 212–219.)
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BOHB , Beta-hydroxybutyrate; FFA , free fatty acids; IGFBP-1 , insulin-like growth factor binding protein 1.
Adenosine Triphosphate Sensitive Potassium Channel Hyperinsulinism
Mutations in the adenosine triphosphate-sensitive potassium (KATP) channel genes are the most commonly identified genetic defects in patients with congenital HI. The ABCC8 and KCNJ11 genes on chromosome 11p encode the two subunits, SUR1 and Kir6.2, of the KATP channel in the plasma membrane of the beta-cell. Potassium efflux through this channel hyperpolarizes the beta-cell plasma membrane and is a key negative regulator of insulin secretion; genetic defects which impair KATP channel activity and preclude channel opening cause persistent depolarization of the plasma membrane and uncontrolled insulin secretion. As described in Chapter 7 , there are three distinct forms of KATP-HI:
-
Biallelic inheritance of two recessive KATP mutations causes diffuse HI with severe neonatal onset that is unresponsive to diazoxide.
-
Recessive KATP channel mutations also can cause focal congenital HI by a two-hit mechanism, involving a paternally transmitted recessive KATP mutation combined with an embryonic somatic mutation in the corresponding maternal gene, resulting in effective paternal 11p uniparental isodisomy for the region containing both KATP and the Beckwith-Wiedemann imprinted genes. The resulting focal area of islet cell adenomatosis contains beta cells with defective KATP channels, resulting in HI.
-
Dominantly inherited KATP channel mutations act in dominant-negative fashion to produce diffuse HI with KATP channels that have varying degrees of impaired channel function. Most dominant KATP mutations are diazoxide responsive, but diazoxide-unresponsive mutations do occur.
The diffuse and focal forms of KATP-HI account for more than 90% of diazoxide-unresponsive cases of congenital HI in early infancy, and are similar in their clinical manifestations. Both may require surgery to maintain safe glucose levels.
Beyond the neonatal period, dominant KATP mutations are more common and are often diazoxide-responsive.
Diazoxide (5–15 mg/kg/day) is the first-line drug for treatment of HI, but is often ineffective for KATP-HI, because it acts as a KATP channel opener. Octreotide may be given by subcutaneous injection at 5 to 15 mcg/kg/day. Longer acting somatostatin analogs, such as lanreotide, have recently been introduced, with some success in older infants. Calcium-channel blockers are not effective. If medical management cannot maintain the plasma glucose concentration greater than 70 mg/dL, with a normal feeding schedule, surgery may be necessary. Surgical treatment for focal KATP-HI can be curative, whereas for diffuse disease even a 95% to 99% pancreatectomy may not cure the hypoglycemia, and insulin-dependent diabetes is a frequent consequence. 18F-fluorodopa positron-emission tomography ( 18 F-L-DOPA PET) scans have been accurate in preoperative localization of a focal lesion.
Glutamate Dehydrogenase Hyperinsulinism
HI can be caused by dominant activating mutations in GLUD1 on 10q, which encodes glutamate dehydrogenase (GDH). This disorder is also known as the HI hyperammonemia syndrome , because the increased GDH enzymatic activity in kidney tubules results in increased renal ammoniagenesis. Hypoglycemia in GDH-HI is usually milder than in KATP-HI, and less likely to present in the newborn period. As is common with dominant genetic disorders, up to 80% of cases with GDH-HI have a de novo mutation. The hyperammonemia in GDH-HI appears to be asymptomatic. However, affected children frequently have brain manifestations, possibly because of increased GDH activity in neurons and altered levels of glutamate or other neurotransmitters: these include absence seizures (generalized epilepsy), behavior disorders, and mild to moderate developmental delay.
In GDH-HI, activating mutations of GDH in the beta cell amplify leucine-triggered production of ATP, leading to closure of KATP channels and insulin release, independent of glucose levels. In affected children, ingestion of high-protein feedings can induce hypoglycemia (leucine-sensitive or protein-sensitive hypoglycemia). In the kidney, the same mutations increase oxidation of glutamate to alpha-ketoglutarate with the release of ammonia.
The diagnosis of GDH-HI is similar to that of other forms of HI; however, persistently elevated plasma ammonia levels (typically 80–120 μmol/L) are specific for this disorder. Because the hyperammonemia is of renal origin, plasma ammonia levels are unrelated to either insulin secretion or plasma glucose levels and are also not related to protein feeding. Thus elevated ammonia levels can be readily demonstrated in casual (random) specimens of plasma. Most patients respond well to diazoxide and do not need surgery.
Glucokinase Hyperinsulinism
Glucokinase (encoded by GCK ) is the enzyme that serves as the glucose sensor in the beta cells of the pancreas. Gain-of-function glucokinase mutations result in a lower glucose threshold for insulin secretion, leading to persistent hypoglycemia (in contrast, GCK loss-of-function mutations produce a higher glucose threshold for insulin release, causing a common form of mild monogenic diabetes (MODY2). At least 15 different dominantly expressed GCK-HI mutations have been reported. Alterations in the enzyme kinetics of individual mutations predict widely different degrees of lowering of glucose threshold, but do not correlate with clinical severity and course. In some cases, GCK-HI mutations present with neonatal hypoglycemia, severe enough to require pancreatectomy to control hypoglycemia; however, some mutation carriers have escaped recognition even into adulthood.
GCK-HI may be especially challenging to diagnose, because fasting plasma glucose levels tend to stabilize at a glucose threshold between 50 and 65 mg/dL. During fasting, if plasma glucose remains at this threshold for an extended period, levels of FFA and BOHB can rise, suggesting a form of ketotic hypoglycemia rather than HI. Plasma ammonia levels are normal in GCK-HI patients and they do not have protein-sensitive hypoglycemia. The response to diazoxide has been only partial and transient in most patients with GCK-HI and some have required pancreatectomy. One report has described good results using a ketogenic diet to prevent symptomatic hypoglycemia; the long-acting somatostatin analog, lanreotide, might be useful in older patients, but experience is limited.
Hexokinase 1 Hyperinsulinism
Hexokinase 1 ( HK1 ) is closely related to glucokinase and carries out the first step in glucose oxidation by phosphorylating glucose to glucose-6-phosphate in most tissues of the body, except for beta cells. In contrast to glucokinase, which has a low affinity for glucose (Km ~ 5 mM) that sets the threshold for glucose stimulation of insulin secretion at around 4 to 4.5 mM (70–80 mg/dL), HK1 has a very high affinity for glucose (Km ~ 1 mM), and its expression in beta cells is therefore normally disallowed. Two reports of congenital HI possibly because of beta-cell expression of HK1 have recently been published. The first report described a large, dominant pedigree with diazoxide-responsive congenital HI, in which linkage analysis identified a shared haplotype on chromosome 10 that included 3 noncoding mutations in the HK1 locus. This family was in one of the original descriptions of congenital HI by McQuarrie in 1953. It was suggested that one or more of these mutations caused HK1 to be expressed in beta cells and to reduce the glucose threshold for insulin secretion to around 55 to 60 mg/dL. In the second report, increased beta-cell expression of HK1 was detected by immunohistochemical staining of islets from several infants who underwent surgery for diazoxide-unresponsive congenital HI; these infants were also suggested to have HI because of a failure of HK1 silencing in beta cells. As described later, failure to silence expression of a “disallowed” beta-cell gene has also been suggested as the mechanism of exercise-induced HI: expression of the pyruvate plasma membrane transporter, MCT1.
Short Chain 3-Hydroxyacyl-Coa Dehydrogenase Hyperinsulinism
Short chain 3-hydroxyacyl-CoA dehydrogenase ([SCHAD], encoded by HADH on chromosome 4 at q22-26) is a mitochondrial fatty acid oxidation enzyme that catalyzes oxidation of short chain 3-hydroxyacyl-CoAs. Levels of SCHAD protein are relatively high in pancreatic beta cells, where it appears to negatively regulate the activity of GDH, the target of the gain-of-function mutations responsible for GDH-HI (the hyperammonemia HI syndrome). Homozygous inactivating mutations of the HADH gene are associated with increased beta-cell GDH activity and cause a form of HI similar to GDH-HI, but without hyperammonemia or specific brain defects. The systemic defect in fatty acid oxidation in SCHAD deficiency leads to accumulation of upstream substrates resulting in diagnostic elevations of urinary organic acids (3-hydroxyglutarate) and plasma acylcarnitines (3-hydroxybutyryl-carnitine). Patients with HI caused by SCHAD deficiency have responded well to treatment with diazoxide.
Hepatocyte Nuclear Factor 4a Hyperinsulinism
Hepatocyte nuclear factor 4a (HNF4A) is a transcription factor important for pancreatic beta-cell development and insulin secretion. Heterozygous inactivating mutations of HNF4A are a well-recognized cause of monogenic diabetes (MODY1). Recently, it was recognized that these same mutations also cause excessive insulin secretion in early life, as manifested by fetal macrosomia and persistent diazoxide-responsive neonatal hyperinsulinemic hypoglycemia. The HI is usually transient, lasting only a few weeks to a few months after birth; however, it may persist for several years into childhood. In the second and third decades, these children may develop the MODY1 form of diabetes, which is responsive to treatment with sulfonylureas. In most cases of HNF4A HI, birthweight has been above average, hypoglycemia occurred within the first days of life, and one parent had a history of MODY-type diabetes. Children with a specific HNF4A mutation, p.Arg76Trp, have additional manifestations, including renal Fanconi syndrome and hepatomegaly and elevated transaminases, suggesting that expression of the GLUT2 transporter in kidney tubules and in liver was impaired by the defect in HNF4A .
Hepatocyte Nuclear Factor 1A Hyperinsulinism
Hepatocyte nuclear factor 1a (HNF1A) is another transcription factor important for beta-cell development. Heterozygous inactivating mutations of HNF1A cause the most common form of monogenic diabetes, MODY3. Several cases of HNF1A mutations causing congenital HI have been reported, several of which also were associated with MODY diabetes in older patients. An interesting, unexplained discrepancy between HNF4A and HNF1A HI is that large for dates birthweight has only been associated with HNF4A , but not HNF1A mutations.
Uncoupling Protein 2 Hyperinsulinism
Uncoupling protein 2 (UCP2) transfers Krebs cycle intermediates out of the mitochondria and favors oxidation of amino acids versus glucose in beta cells, liver, and other tissues. Loss-of-function mutations of UCP2 may enhance ATP generation from glucose and consequently amplify insulin responses to glucose stimulation, sufficiently as to cause hyperinsulinemic hypoglycemia. Several cases have been reported, which have generally responded to treatment with diazoxide.
Exercise-Induced Hyperinsulinism
A total of 13 patients belonging to three families have been found with dominantly inherited exercise-induced hyperinsulinemic (EIHI) hypoglycemia following periods of intense anaerobic exercise. Clinical presentations have varied, with some cases having severe hypoglycemic episodes from infancy; some presenting with hypoglycemic syncope after exercise, as adolescents; and some only mildly affected, as adults. Most patients maintained normal glucose levels during prolonged fasting. Provocative testing, with brief, intense bicycle exercise, induced the expected rise in plasma lactate and pyruvate levels, but markedly increased plasma insulin concentrations for about 10 minutes after the exercise, causing hypoglycemia over the next 45 minutes. Intravenous infusion of pyruvate stimulated a similar rise in insulin, suggesting that the defect reflected an abnormal beta-cell responsiveness to pyruvate. Recurrent hypoglycemia was only partially preventable with diazoxide treatment.
Excessive insulin secretion in EIHI occurs because of mutations upstream of the promoter region SLC16A1 that allows the MCT1 monocarboxylate transporter to be expressed on the beta-cell plasma membrane. Normally, expression of MCT1 is “disallowed” in beta cells to prevent pyruvate and lactate from acting as insulin secretagogues.
Syndromic Forms of Congenital Hyperinsulinism
Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by embryonic mosaic mutations of an imprinted region on 11p, which is close to the location of the beta-cell KATP channel genes, SUR1 and Kir6.2 . The BWS locus includes growth-inhibiting genes expressed on the maternal chromosome (H19, P57) and growth-promoting genes ( IGF2 ) expressed on the paternal chromosome; expression of these genes is controlled by two imprinting control sites. Although BWS has been associated with HI for many years, recently it has been found that most cases of BWS with persistent HI are associated with paternal isodisomy for the 11p region (11pUPD overgrowth), which is the cause of around 20% of BWS cases. The histopathology in these cases shows islet cell overgrowth (adenomatosis), which may involve nearly the entire pancreas. Some cases are responsive to diazoxide, but hypoglycemia in some may not be controllable with diazoxide and may require more intensive medical management with octreotide and continuous feedings or pancreatectomy. Some cases of 11pUPD BWS also have a paternally transmitted recessive KATP channel mutation; these cases can have severe HI and unusually high glucose requirements. The possibility of 11pUPD BWS should be suspected in infants with HI who have features of BWS, such as hemihypertrophy, macroglossia, or umbilical hernia.
Kabuki Syndrome
Kabuki syndrome is associated with recognizable dysmorphic features including facial features resembling a Kabuki actor mask and caused by somatic mosaic mutations in either MLL2 ( KMT2D ) or KDM6A , two genes which regulate chromatin methylation. A proportion of infants with Kabuki syndrome have persistent hypoglycemia caused by HI, which may either be responsive or nonresponsive to treatment with diazoxide.
Turner Syndrome
Turner syndrome has been reported to be associated with congenital HI for several decades. A recent study found that the frequency of Turner syndrome in a large series of children with HI was increased ~ 50-fold, indicating that the risk of HI in Turner syndrome was around 1 in 1000 compared with the risk of HI in the general population of 1 in 40,000. Some of the Turner syndrome cases were diazoxide responsive, but others failed to respond to diazoxide and required pancreatectomy. The only consistent chromosomal anomaly in Turner syndrome girls with HI was a 45 XO karyotype, suggesting that loss of a gene on the X-chromosome was the cause of the HI. A possible candidate gene is KDM6A , a pseudoautosomal X-chromosome gene, because inactivating mutations of KDM6A are one of the causes of Kabuki syndrome in which there is also an increased frequency of HI.
Carbohydrate-Deficient Glycoprotein Hyperinsulinism
Congenital disorders of glycosylation (CDG) are caused by recessively inherited loss-of-function mutations in genes that regulate glycosylation of proteins. Most produce syndromic diseases affecting multiple organ systems, including brain, skeleton, liver, and kidney. Hypoglycemia resulting from HI has been reported in children with three of the identified defects of N-glycosylation: CDG Ia, Ib, and Id (OMIM IDs: 601785, 602579, and 601110). Most cases of CDG-HI have been identified in the newborn period, but some have been diagnosed later in infancy or early childhood. CDG-HI is usually suspected in a child with a dysmorphic facies and manifestations affecting multiple other organ systems, including—especially the brain, liver, gut, and skeleton. In all three types, cases have been reported in which hyperinsulinemic hypoglycemia was the presenting or dominant problem. The mechanism of excessive insulin production has not been determined.
Phosphomannomutase 2 (PMM2)-CDG (CDG-Ia) is the most common type of CDG and involves deficient activity of phosphomannomutase 2 resulting from mutations of PMM2 . Most patients have severe developmental delay, cerebellar hypoplasia, hypotonia, and seizures. Protein-losing enteropathy and liver disease contribute to failure to thrive. Deficient levels of antithrombin III can cause thromboses. Dysmorphic features are common and may be subtle or obvious, including unusual fat distribution and inverted nipples. Hyperinsulinemic hypoglycemia occurs in only a minority of patients, but can be mild or severe enough to warrant pancreatectomy.
Phosphomannose isomerase (MPI)-CDG (CDG-Ib) involves deficient activity of phosphomannose isomerase resulting from mutations of MPI . Unlike CDG-1a, the central nervous system is spared and hyperinsulinemic hypoglycemia is a common feature, presenting in the first days of life or later in the first year. Liver disease and protein-losing enteropathy are usually the dominant clinical problems. Some children have had cyclic vomiting. Clinical severity is variable, and mildly affected adults have been diagnosed. Oral mannose in doses of up to 150 mg/kg/day can correct most of the clinical abnormalities, making MPI-CDG the only CGD with a specific treatment.
ALD3-CDG (CDG-Id) involves deficient activity of mannosyltransferase 6 resulting from mutations of ALD3 . Clinical features resemble those of PMM2-CDG, with severe central nervous system damage. One case with severe neonatal hyperinsulinemic hypoglycemia has been reported, but whether it was a direct result of the CDG or a consequence of perinatal stress is unknown.
PMG-1 reversibly converts glucose-6-P to glucose-1-P and is required both for glycogen formation and degradation. Recessive inactivating mutations of PGM1 cause a syndrome of dysmorphic features, short stature, and fasting hyperketonemic hypoglycemia. In addition to abnormalities in protein glycosylation (hence the designation of CDG-It), hyperinsulinemic hypoketonemic hypoglycemia occurs when patients are fed. Deficiency of PGM1 impairs both the synthesis and breakdown of liver glycogen (hence the fasting hyperketonemic hypoglycemia and the labeling of the disorder as GSD type 14 ). However, deficiency of PGM1 in the beta cell appears to cause an exaggerated insulin response to a glucose load, leading to postprandial hyperinsulinemic hypoglycemia. The diagnosis can be made by screening tests for abnormalities in transferrin glycosylation. Treatment with diazoxide has not been effective in controlling postprandial hyperinsulinemic hypoglycemia, but low glycemic index feedings, uncooked cornstarch (UCS), or continuous low-dose glucose infusions have been more successful. Because the defect potentially impairs synthesis of galactose, treatment with galactose supplements have been tried with some success in correcting abnormalities of transferrin glycosylation.
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