INTRODUCTION — Hypoglycemic disorders are rare, but their consequences, particularly for children, can be severe and disabling. Severe hypoglycemia may result in seizures and brain damage, which lead to developmental delays, physical and learning disabilities, and, in rare cases, death [1,2]. Given these severe consequences, the prompt diagnosis and appropriate management of hypoglycemic disorders in children are crucial.
Causes of hypoglycemia in infants and children are discussed below. The diagnostic approach to hypoglycemia in infants and children and other related content can be found in the following topic reviews:
Definition of hypoglycemia — Hypoglycemia is defined as a plasma glucose level that is low enough to cause signs and symptoms of brain dysfunction (neuroglycopenic symptoms).
Because the response to hypoglycemia occurs across a range of plasma glucose concentrations, hypoglycemia cannot be defined as a single plasma concentration. However, for diagnostic purposes, a working definition of hypoglycemia is a plasma glucose <50 mg/dL (2.8 mmol/L), as documented by a laboratory-quality assay. This threshold approximates a value where neuroglycopenic symptoms may develop and is useful for patients who cannot communicate their symptoms. (See "Approach to hypoglycemia in infants and children", section on 'Diagnosis of hypoglycemia'.)
Categories of hypoglycemic disorders
The differential diagnosis of hypoglycemic disorders is broad. However, many of the disorders have specific clinical and laboratory features that provide important diagnostic clues. Because the vast majority of hypoglycemic events are triggered by fasting, hypoglycemic disorders can be categorized by their metabolic and hormonal profiles in response to fasting (algorithm 1) . These categories are:
●Fatty acid oxidation disorders
●Ketotic hypoglycemic disorders
●Disorders of gluconeogenesis
●Other causes, including toxic ingestions and acute or critical illness
Specific causes within each of these categories are outlined in the table (table 1) and detailed below.
INSULIN-MEDIATED DISORDERS — Insulin-mediated hypoglycemic disorders are characterized by (algorithm 1):
●Suppressed free fatty acids
●Positive glycemic response to glucagon
Hyperinsulinism — Hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children . Dysregulated insulin secretion by the beta cells of the pancreas causes severe and recurrent hypoglycemia and can be monogenic (resulting from genetic defects affecting important factors in the regulation of insulin secretion), transient (resulting from perinatal stress), or syndromic. Given the severe hypoglycemia, and because of the lack of alternative fuels (ketones), HI carries a high risk of neurologic damage and developmental delays, with up to 50 percent of children developing neurocognitive abnormalities [1,5].
HI can be further categorized by the underlying mechanism:
●Congenital (monogenic) hyperinsulinism – The congenital form of HI results from genetic defects in insulin secretory pathways of the beta cell. The most common and severe form is due to inactivating mutations of the beta cell adenosine triphosphate (ATP)-sensitive potassium channel (table 2) [6,7]. This form is typically not responsive to diazoxide, the first-line agent for the treatment of HI, and has two distinct histologic subtypes: diffuse and focal [8,9]. Through specialized imaging and surgery, infants with the focal form can be cured of their HI [10,11]. These disorders are discussed in detail in separate topic reviews. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism" and "Treatment and outcomes of congenital hyperinsulinism".)
●Perinatal stress-induced hyperinsulinism – Stress in utero or during labor and delivery can lead to a transient form of HI, which resolves within the first three to six months of life . (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Hyperinsulinism'.)
●Syndromic hyperinsulinism – HI may also occur in the setting of specific syndromes, such as Beckwith-Wiedemann syndrome or Kabuki syndrome (table 3) [13,14]. (See "Beckwith-Wiedemann syndrome" and "Vitiligo: Pathogenesis, clinical features, and diagnosis", section on 'Genetic syndromes'.)
In neonates with panhypopituitarism, the biochemical response to fasting and the glucagon stimulation test are identical to those with neonatal HI. Panhypopituitarism should be suspected in neonates with hypoglycemia who have midline defects (eg, choanal atresia or cleft palate) or microphallus. After the neonatal period, the biochemical response to fasting in children with panhypopituitarism includes ketosis. (See 'Hormone deficiencies' below.)
Assessment of pituitary function is crucial prior to starting empiric therapy with growth hormone and/or cortisol. The treatment of panhypopituitarism with hormone replacement resolves the hypoglycemia. (See "Causes of central adrenal insufficiency in children", section on 'Permanent central adrenal insufficiency'.)
Insulinoma — Insulinomas are insulin-secreting islet cell tumors and are typically benign. They sometimes occur in the setting of multiple endocrine neoplasia type 1 (MEN1). These tumors are a rare cause of hypoglycemia in children but should be suspected when persistent and recurrent hypoglycemia presents in adolescence, although cases have been reported in children as young as two years old. In children with insulinomas, MEN1 mutations are more common than in adults with insulinomas; however, insulinomas as part of MEN1 account for fewer than 50 percent of cases in pediatrics .
Given their frequently small size and variable locations, multiple imaging modalities may be necessary for localization . Surgical resection of the tumor is curative. Genetic testing for MEN1 should be performed in any child presenting with an insulinoma . (See "Insulinoma".)
Factitious hypoglycemia — Factitious or induced hypoglycemia refers to intentional administration of insulin or an oral hypoglycemic medication by a parent, caregiver, or by the child him- or herself. The diagnosis should be suspected in children with severe hypoglycemia that has an abrupt onset and does not have consistent triggers such as fasting or illness. Specialized insulin assays and sulfonylurea toxicology studies are often necessary to confirm this diagnosis . (See "Medical child abuse (Munchausen syndrome by proxy)" and "Approach to hypoglycemia in infants and children", section on 'Low ketones and low free fatty acids'.)
Oral hypoglycemic agents are also a common accidental ingestion by young children. (See 'Ingestions' below.)
Disorders of glycosylation — Congenital disorders of glycosylation are caused by defects in the enzymes responsible for glycosylation of proteins, the process through which glycans are attached to proteins . These multisystem disorders have a broad spectrum of clinical manifestations, including hyperinsulinemic hypoglycemia, developmental delay, and congenital malformations . Specific disorders of glycosylation associated with hyperinsulinemic hypoglycemia include phosphomannomutase 2 deficiency (MIM #212065), phosphoglucomutase 1 deficiency (MIM #614921), and mannosephosphate isomerase deficiency (MIM #602579). (See "Inborn errors of metabolism: Classification", section on 'Congenital disorders of glycosylation'.)
FATTY ACID OXIDATION DISORDERS — Fatty acid oxidation disorders are characterized by (algorithm 1):
●Elevated free fatty acids
They are caused by genetic defects in the enzymatic pathways that control fatty acid transport and beta-oxidation in the mitochondria ; the most common is medium-chain acyl-CoA dehydrogenase deficiency (MCADD; MIM #201450), although there are many other less common disorders.
The clinical presentation of fatty acid oxidation disorders is variable, ranging from mild hypotonia to a Reye-like syndrome (acute liver failure and encephalopathy) and sudden unexpected infant death. The more severe forms are characterized by hypoglycemia, hyperammonemia, elevated serum transaminase levels, and liver failure, as well as cardiac and skeletal myopathy. Prolonged fasting can provoke a life-threatening metabolic crisis. Therefore, fatty acid oxidation disorders should be excluded before performing a diagnostic fast (see "Approach to hypoglycemia in infants and children", section on 'Diagnostic fast'). The majority of these disorders are now detected through newborn screening and are confirmed using genetic testing . (See "Overview of fatty acid oxidation disorders".)
KETOTIC HYPOGLYCEMIC DISORDERS — This category of hypoglycemic disorders is characterized by elevated ketones (algorithm 1).
Disorders of glycogen metabolism — The glycogen storage disorders (GSD), a large heterogenous group of disorders, result from defects in the enzymes that regulate glycogen breakdown and synthesis in the liver and muscle. GSDs present with variable degrees of hypoglycemia, ketosis, elevated serum transaminase levels, and hepatomegaly (except in GSD type 0, glycogen synthase deficiency). Failure to thrive is frequently present.
The GSDs that primarily affect the liver and lead to hypoglycemia are types 0, I, III, VI, and IX :
●GSD type I is also a disorder of gluconeogenesis and is discussed in more detail below. (See 'Glycogen storage disease type I' below.)
●GSD type III is typically diagnosed in infancy due to its more severe phenotype . It is also characterized by hyperlipidemia, and type IIIa (accounting for 85 percent of cases in the United States) affects skeletal and cardiac muscle .
●GSD types 0, VI, and IX typically present with milder hypoglycemia and liver abnormalities and may not be detected until early childhood.
Treatment for GSD involves avoidance of prolonged fasting and administration of supplemental uncooked cornstarch and a high-protein diet. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
Hormone deficiencies — After the newborn period, patients with deficiencies of cortisol and growth hormone may present with ketotic hypoglycemia. However, in the neonate, hormone deficiencies or hypopituitarism have laboratory findings identical to those found in hyperinsulinism (suppressed ketones, suppressed free fatty acids, and a glycemic response to glucagon). (See 'Hyperinsulinism' above.)
●Cortisol deficiency may result from primary adrenal dysfunction (congenital or acquired adrenal dysfunction) or central nervous system dysfunction (deficiency of adrenocorticotropic hormone, with or without other pituitary hormone deficiencies).
●Growth hormone deficiency may be associated with hypoglycemia during infancy, especially in those with concurrent cortisol deficiency. Hypoglycemia is not a common manifestation of growth hormone deficiency in older children. (See "Diagnosis of growth hormone deficiency in children", section on 'Clinical presentation'.)
●Combined pituitary hormone deficiencies (or panhypopituitarism) should be suspected in children with optic nerve hypoplasia or midline defects, such as cleft lip or palate, central maxillary incisor, or microphallus. Replacement of the absent hormones prevents the hypoglycemia.
Ketone utilization defects — Ketone utilization defects are rare disorders characterized by recurrent episodes of ketoacidosis and persistent ketosis. Mild hypoglycemia has been described in these individuals. They include succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency (MIM #245050), alpha-methylacetoacetic aciduria (MIM #203750), and monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095).
Idiopathic ketotic hypoglycemia — Idiopathic ketotic hypoglycemia is characterized by episodes of symptomatic hypoglycemia without evidence of an endocrine or metabolic cause. It occurs most commonly in toddlers and young children and is characterized by decreased fasting tolerance.
This form of ketotic hypoglycemia is a diagnosis of exclusion, and it is important to rule out a mild GSD or ketone utilization defect by evaluating the response to fasting during a diagnostic fast, evaluating other parameters (liver function, lipids, etc), and genetic testing when indicated . This evaluation is particularly important in children with recurrent and severe hypoglycemic episodes and other features including short stature, hypertriglyceridemia, hepatomegaly, etc.
Idiopathic ketotic hypoglycemia resolves with age and typically does not require specific treatment beyond limiting prolonged fasting.
DISORDERS OF GLUCONEOGENESIS — Disorders of gluconeogenesis are characterized by elevated lactate concentrations at the time of hypoglycemia. Gluconeogenesis is the process whereby the liver converts substrates, such as lactate, pyruvate, alanine, and glycerol, to glucose, and it plays a crucial role in maintaining euglycemia during fasting. Defects in the enzymes of the gluconeogenic pathway result in the disorders of gluconeogenesis (figure 1). They are characterized by impaired hepatic glucose production and significant metabolic abnormalities from the accumulation of the gluconeogenic substrates in the liver.
Glycogen storage disease type I — Glycogen storage disease (GSD) type I (MIM #232200) results from deficiency of glucose-6-phosphatase (G6Pase), which catalyzes the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6Pase gene lead to GSD type Ia and account for over 80 percent of the cases . GSD type Ib is caused by defects in the G6Pase transporter . Children with GSD type I present with severe hypoglycemia, marked hepatomegaly, and failure to thrive; those with GSD type Ib also have intermittent neutropenia and neutrophil dysfunction in addition to the other features . Metabolic abnormalities include elevations of lactate, triglycerides, and uric acid. Aminotransferases are usually elevated. With fasting, children with GSD type I are at risk for rapid onset of hypoglycemia and severe lactic acidosis, which can be life-threatening. The diagnosis should be suspected in children with hypoglycemia and these characteristic metabolic abnormalities and should be confirmed through genetic testing. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)
Avoidance of fasting is crucial in the management of GSD type I. Affected infants are typically treated with frequent feeds or a continuous infusion of intragastric dextrose. After 9 to 12 months of age, children can be transitioned to a regimen of frequent feeds and enteral administration of uncooked cornstarch given every four to six hours . (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)", section on 'Management'.)
Fructose-1,6-bisphosphatase deficiency — Fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphatase into fructose-6-phosphate, and deficiency of this enzyme impairs the gluconeogenic pathway (MIM #229700).
Clinical features of this disorder are similar to GSD type I and include hypoglycemia, severe lactic acidosis, hyperuricemia, hypertriglyceridemia, and failure to thrive . However, children with fructose-1,6-bisphosphatase deficiency have intact glycogenolysis and therefore present with only mild to moderate hepatomegaly and normal transaminase levels. The disease may present during the neonatal period or early infancy. However, the diagnosis can be delayed until early childhood, when individuals present with a metabolic crisis in the setting of fasting or acute illness.
The diagnosis is suspected based on the characteristic biochemical abnormalities and is confirmed with genetic testing of the FBP1 gene, which encodes fructose-1,6-bisphosphatase (figure 2). Infants with fructose-1,6-bisphosphatase deficiency may require overnight continuous intragastric dextrose or feeds, while older children are managed with frequent feeds and uncooked cornstarch . Illness or inability to tolerate oral intake may precipitate a life-threatening metabolic crisis and requires hospitalization for administration of intravenous dextrose.
Pyruvate carboxylase deficiency — Pyruvate carboxylase (PC) converts pyruvate to oxaloacetate, which is the first step of gluconeogenesis.
Children with PC deficiency (MIM #266150) present with seizures, developmental delay and failure to thrive. Metabolic abnormalities include hypoglycemia, lactic acidosis, hyperammonemia, and elevated plasma concentrations of pyruvate and alanine . Serum and urine amino acids may show abnormalities of alanine, aspartate, citrulline, and lysine. The diagnosis is confirmed through sequencing of the PC gene.
PC deficiency can be categorized into three overlapping phenotypic subgroups: type A (infantile), type B (severe neonatal), and type C (intermittent or benign). The prognosis for types A and B is poor, with a high mortality rate in infancy and early childhood [34,35]. Treatments for PC deficiency include frequent feeds, amino acid supplementation, and bicarbonate. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Lactate and pyruvate'.)
Phosphoenolpyruvate carboxykinase deficiency — Phosphoenolpyruvate carboxykinase (PEPCK) deficiency (MIM #261680) is an extremely rare disorder, with only a handful of cases reported in the literature . PEPCK catalyzes the conversion of oxaloacetate into phosphoenolpyruvate and is present in both the mitochondria and the cytosol.
Children with PEPCK deficiency present with episodes of severe lactic acidosis and hypoglycemia. Multisystem dysfunction has been reported, including failure to thrive, hypotonia, developmental delay, liver failure, renal tubular acidosis, and cardiomyopathy. The diagnosis is made with mutational analysis of the mitochondrial and cytosolic forms of the PEPCK gene.
Galactosemia — Galactosemia (MIM #230400) is caused by one of several defects in the enzymes responsible for converting galactose to glucose in the liver. The most common and severe form is caused by a deficiency of galactose-1-phosphate uridyl transferase (GALT). Individuals with galactosemia are unable to metabolize galactose. They are also unable to metabolize lactose, which is a disaccharide composed of galactose and glucose and is the major dietary carbohydrate for infants who are fed breast milk or cow's milk-based infant formulas.
Clinical features of galactosemia include hypoglycemia, diarrhea, and vomiting after ingestion of lactose or galactose. Infants may present with failure to thrive or sepsis. Most infants with galactosemia are identified through newborn screening. Galactosemia is discussed in detail in a separate topic review. (See "Galactosemia: Clinical features and diagnosis".)
Hereditary fructose intolerance — Hereditary fructose intolerance (HFI, MIM #229600) is caused by deficiency of aldolase B, which catalyzes the cleavage of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde in the pathway of fructose metabolism (figure 2). This results in accumulation of fructose-1-phosphate, as well as fructose-1,6-bisphosphate, and thereby impairs the glycolytic and gluconeogenic pathways .
HFI typically presents when fructose or sucrose (a disaccharide composed of glucose and fructose) is introduced into the diet. Children present with hypoglycemia and vomiting following fructose ingestion . Additional clinical manifestations include hepatomegaly, lactic acidosis, and failure to thrive. If exposure to fructose continues, the affected individual may develop liver failure and renal tubular dysfunction. Undiagnosed children may develop a self-protective aversion to fructose and sucrose-containing foods . Diagnosis can be made through sequencing of the ALDOB (aldolase B, fructose-bisphosphate) gene. The mainstay of treatment is a fructose-free diet, and adherence to such a diet can reverse or prevent nearly all of the manifestations of the disease.
OTHER CAUSES OF HYPOGLYCEMIA
Ingestions — Intentional or unintentional ingestion of various agents can cause hypoglycemia in infants and children, including a variety of drugs.
●Oral hypoglycemic agents – Sulfonylureas such as glipizide or glyburide stimulate insulin secretion by their action on the beta cell adenosine triphosphate (ATP)-sensitive potassium channels and are indicated for the treatment of type 2 diabetes mellitus. Sulfonylurea ingestion must be considered in any child who presents with an abrupt onset of hypoglycemia, laboratory findings concerning for an insulin-mediated process, and possible exposure to the drugs. A specialized screen for sulfonylureas is necessary to make this diagnosis as it is not detected in many routine drug screens. (See "Sulfonylurea agent poisoning" and "Medical child abuse (Munchausen syndrome by proxy)".)
●Ethanol – Ingestion of ethanol, particularly by young children, can cause severe hypoglycemia, seizures, and, in some cases, death. Hypoglycemia from ethanol is caused by oxidation of ethanol, resulting in increased NADH:NAD (nicotinamide adenine dinucleotide) ratio, which impairs conversion of lactate to pyruvate and thus inhibits gluconeogenesis in the liver . Ethanol ingestion should be considered in hypoglycemic children who have a metabolic acidosis with increased anion gap and elevated lactate. (See "Approach to the child with occult toxic exposure" and "Ethanol intoxication in children: Clinical features, evaluation, and management".)
●Salicylates – Hypoglycemia from the ingestion of salicylates or their ester derivatives has been reported in children, although it is likely a rare occurrence . Suggested mechanisms include stimulation of insulin release or inhibition of hepatic gluconeogenesis. Salicylates uncouple oxidative phosphorylation in skeletal muscle, leading to pyrexia and metabolic acidosis. Clinical features of salicylate ingestion include vomiting, confusion, delirium, and hyperventilation. The diagnosis is confirmed by measurement of plasma salicylate concentrations. (See "Salicylate poisoning in children and adolescents".)
●Beta blockers – Beta blockers may increase susceptibility to hypoglycemia through blunting of the typical autonomic response to hypoglycemia when appetite is decreased (for example, during a viral illness in young children) .
●6-mercaptopurine – Fasting hypoglycemia has been seen in children receiving 6-mercaptopurine (6-MP) as part of their chemotherapeutic regimen. The mechanism of hypoglycemia is unknown. Switching from evening to morning administration has successfully prevented the hypoglycemia .
●Ackee or lychee fruit – Ingestion of unripe ackee fruit can cause hypoglycemia associated with vomiting, seizures, and coma; this is known as Jamaican vomiting sickness . The ackee fruit is a staple in the Jamaican diet; the unripe ackee fruit contains hypoglycin, which impairs fatty acid oxidation. A similar mechanism may underlie toxicity from ingestion of unripe lychee fruit, especially by undernourished children; an association with epidemics of acute encephalitis syndrome in malnourished children in India has been suggested [46,47].
Acute or critical illness — In some patients, hypoglycemia is the consequence of an underlying critical illness, which is either already known or is readily identified during the initial evaluation. Important causes include:
●Liver failure – Children with severe acute liver failure from any cause often develop hypoglycemia due to impaired hepatic gluconeogenesis and glycogenolysis. The causes of acute liver failure vary with age. (See "Acute liver failure in children: Etiology and evaluation".)
Hypoglycemia is a particularly prominent feature of certain specific causes of acute liver failure. As an example, a fatty acid oxidation disorder may present with hypoglycemia, acute liver failure, and rapidly progressive encephalopathy. Reye syndrome has a similar presentation, although this syndrome is now rare. (See "Overview of fatty acid oxidation disorders" and "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)
●Sepsis – Contrary to common belief, sepsis is not a frequent cause of previously undiagnosed hypoglycemia in children . Further, hypoglycemia is not among the common signs of sepsis . However, when present, hypoglycemia is a predictor of poor outcome in septic infants . Of note, in the developing world, hypoglycemia is a common complication of intercurrent infections including severe malaria; thus, screening for hypoglycemia is important in such settings . (See "Septic shock in children: Rapid recognition and initial resuscitation (first hour)" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)
●Other – Diarrheal disease in the setting of malnutrition can result in hypoglycemia. The pattern and laboratory features are similar to those of children with idiopathic ketotic hypoglycemia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in infants and children".)
●The differential diagnosis of hypoglycemic disorders in children is broad (table 1). These disorders can be categorized by their metabolic and hormonal profiles during the hypoglycemic episode or in response to fasting (algorithm 1). This categorization allows for rapid and accurate diagnosis in the majority of cases. (See 'Categories of hypoglycemic disorders' above and "Approach to hypoglycemia in infants and children".)
●Insulin-mediated disorders are characterized by suppressed ketones and free fatty acids as well as a positive glycemic response to glucagon. They include congenital hyperinsulinism (the most common cause of hypoglycemia in children), insulinoma, and factitious hypoglycemia. (See 'Insulin-mediated disorders' above.)
●Fatty acid oxidation disorders are characterized by suppressed ketones with elevated free fatty acids. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder. (See 'Fatty acid oxidation disorders' above.)
●Ketotic hypoglycemic disorders are characterized by elevated ketones and include the glycogen storage disorders (GSDs), cortisol and growth hormone deficiencies, and idiopathic ketotic hypoglycemia. (See 'Ketotic hypoglycemic disorders' above.)
●Disorders of gluconeogenesis are characterized by elevated lactate. Examples of these disorders are GSD type I and fructose-1,6-bisphosphonate deficiency. (See 'Disorders of gluconeogenesis' above.)
●Other causes of hypoglycemia include ingestions, such as sulfonylureas or ethanol, and acute or critical illnesses, especially liver failure, sepsis, and severe malaria. (See 'Other causes of hypoglycemia' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Agneta Sunehag, MD, PhD, and Morey W Haymond, MD, who contributed to an earlier version of this topic review.