INTRODUCTION — Hypoglycemic disorders are rare, but their consequences, particularly for children, can be severe and disabling. 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.
The differential of hypoglycemic disorders is broad, and it is essential to have a systematic approach when evaluating a child with hypoglycemia. The vast majority of hypoglycemic events in infants and children with hypoglycemic disorders occur during periods of fasting. This allows for categorization of hypoglycemia disorders by their specific profiles of metabolic fuels and hormones in the fasting state or during an episode of spontaneous hypoglycemia . Therefore, a diagnosis can be rapidly and accurately obtained by assessing the child's metabolic and hormonal response to fasting (algorithm 1).
Glucose homeostasis and the diagnostic approach to hypoglycemia in infants and children will be discussed here. Other topics with related content include:
GLUCOSE HOMEOSTASIS IN NORMAL INFANTS AND CHILDREN
Glucose is the preferred fuel of the brain, which can only store trivial amounts of glucose in the form of glycogen. To ensure an adequate supply of glucose to the brain, the body must successfully adapt to fasting. Multiple systems regulate glucose homeostasis and control the transition from the fed to fasting state. Abnormalities in these "fasting regulatory systems" result in the disorders of hypoglycemia.
In response to fasting, key changes in the endocrine system occur: insulin is suppressed and the serum concentrations of the counterregulatory hormones (glucagon, cortisol, growth hormone, and epinephrine) rise. These hormonal changes activate the three metabolic "fasting systems" (glycogenolysis, gluconeogenesis, lipolysis and ketogenesis), which lead to increased hepatic glucose production, a gradual decrease in glucose utilization, and an increase in availability of alternative fuels (table 1):
●Initially, during fasting, the liver is the primary source of glucose, generated through breakdown of glycogen and production of glucose from amino acids, glycerol, and lactate via gluconeogenesis.
●With more prolonged fasting, the body switches to adipose tissue as the major source of fuel . Lipolysis and ketogenesis lead to an increase in free fatty acids (FFAs) and the ketone bodies beta-hydroxybutyrate (BOHB) and acetoacetate.
●As glucose production declines and ketones levels increase, the brain gradually switches to ketones as its main fuel .
Glucose homeostasis and the metabolic response to fasting do not differ significantly between infants after the first two to three days of life, children, and adults. However, glucose levels decline more rapidly and the transition to ketogenesis occurs earlier in infants and young children compared with older children and adults, given infants' relatively larger brain volume and higher glucose utilization rates. The transition to ketogenesis occurs after fasting for 12 to 18 hours in neonates and infants, while in older children and adults, this transition may take up to 24 to 48 hours of fasting .
Symptoms of hypoglycemia can be divided into neurogenic and neuroglycopenic symptoms:
●Neurogenic (autonomic) symptoms are caused by the sympathetic nervous system's response to hypoglycemia and appear when the plasma glucose is less than 55 to 60 mg/dL. Manifestations are sweating, tremor, palpitations, tachycardia, and hunger.
●Neuroglycopenic symptoms result from insufficient supply of glucose to the brain, leading to brain dysfunction. They include lethargy, confusion, irritability, loss of consciousness, and seizure. Neuroglycopenic symptoms typically occur when the plasma glucose falls below 50 mg/dL.
Although neurogenic symptoms may serve as warnings before more severe hypoglycemia occurs, repeated exposure to hypoglycemia can blunt or eliminate these symptoms and the counterregulatory hormone response to hypoglycemia. This is known as hypoglycemic-associated autonomic failure (HAAF) or "hypoglycemia unawareness" and may result in individuals presenting with lower plasma glucose values and neuroglycopenic symptoms . Features of HAAF have been demonstrated to occur even in infants . (See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus", section on 'Symptoms and signs'.)
●Older children and adults – Hypoglycemia in these age groups typically demonstrates the Whipple triad:
•Symptoms and signs consistent with hypoglycemia
•A documented low plasma glucose concentration
•Resolution of the symptoms with normalization of the glucose concentration
●Infants and toddlers – Symptoms in these age groups are frequently nonspecific and include irritability, lethargy, poor feeding, cyanosis, and tremor or jitteriness. Commonly, infants manifest no symptoms of hypoglycemia until they present with a hypoglycemic seizure.
Many hypoglycemia disorders have specific clinical features that can provide important clues to their diagnosis. (See "Causes of hypoglycemia in infants and children".)
INDICATIONS FOR EVALUATION — In 2015, the Pediatric Endocrine Society, through a committee composed of pediatric endocrinologists and neonatologists, published recommendations for the evaluation and management of hypoglycemia in neonates, infants, and children . The recommendations outline which neonates, infants, and children should be evaluated for a hypoglycemic disorder according to their ability to communicate symptoms:
●For neonates, evaluate those who are suspected to be at high risk of having a persistent hypoglycemia disorder (table 2). The diagnostic evaluation should be performed when the infant is at least 48 hours of age.
●For infants and younger children who are unable to reliably communicate symptoms, evaluate those whose plasma glucose concentrations are <60 mg/dL (3.3 mmol/L), as documented by a laboratory-quality assay (a point-of-care test is not sufficient).
●For children who are able to communicate their symptoms, evaluate those who demonstrate Whipple triad (symptoms consistent with hypoglycemia, low plasma glucose concentration, and resolution of symptoms with normalization of plasma glucose). (See 'Clinical features' above.)
DIAGNOSIS OF HYPOGLYCEMIA — Hypoglycemia is defined as a plasma glucose concentration low enough to cause signs and symptoms of brain dysfunction (neuroglycopenia). Because the response to hypoglycemia occurs across a range of plasma glucose concentrations and signs of hypoglycemia are not reliably identifiable, especially in young children, and vary among individuals, hypoglycemia cannot be defined as a single plasma glucose concentration. However, a threshold to obtain diagnostic data and a therapeutic threshold goal are presented below:
●Normal plasma glucose – After the first week of life, the normal range for plasma glucose is 70 to 100 mg/dL (3.9 to 5.6 mmol/L). Normal newborns experience a period of "transitional" hypoglycemia during the first 48 to 72 hours of life. A study of 68 healthy full-term newborns found a mean plasma glucose concentration of 59±11 mg/dL during the first 48 hours of life. The plasma glucose concentration increased to a mean of 82±12 mg/dL by 72 to 96 hours of life [10-12].
●Diagnostic threshold – The threshold for obtaining diagnostic data (often referred to as the "critical sample") and for confirming a diagnosis of hypoglycemia is <50 mg/dL (2.8 mmol/L), as documented by a laboratory-quality assay. This threshold is sufficiently low to avoid false-positive results but is unlikely to cause lasting neurologic sequelae.
●Treatment goal – To provide a margin of safety, the treatment goal for children with hypoglycemic disorders is to maintain a plasma glucose >70 mg/dL (3.9 mmol/L). (See 'Treatment' below.)
The immediate management of a child with hypoglycemia involves rapid normalization of the plasma glucose concentration via oral carbohydrates and/or parenteral glucose (table 3). If the child's mental status is appropriate and a blood sample can be obtained rapidly, diagnostic data can be collected prior to therapeutic invention, if possible.
●Blood – When hypoglycemia is suspected based on symptoms and point-of-care glucose testing, the condition should be confirmed via venous plasma glucose. Additionally, a sample should be obtained to measure major metabolic fuels and counterregulatory hormones when the plasma glucose is <50 mg/dL (2.8 mmol/L) because this is the crucial step to establishing a specific etiology. If sulfonylurea ingestion is suspected, specific toxicology studies should also be sent. (See 'Critical samples' below.)
●Urine – The first urine voided during or immediately after the hypoglycemic event should be collected and tested for ketones (if blood ketones cannot be measured) and urine organic acids.
●Conscious patient – If the child is conscious and cooperative, 15 g (or 0.2 g/kg for infants) of rapid-acting carbohydrate should be given by mouth. This amount can be supplied by 4 ounces of juice, a tube of glucose gel, or four glucose tablets. Obtaining intravenous access is recommended in the event that the child's glucose fails to respond to the oral intervention.
●Patient with altered consciousness – If the child is unconscious or not judged as safe to take oral carbohydrates, intravenous dextrose should be administered:
•Initial bolus – 2 mL/kg of dextrose 10% (0.2 g dextrose/kg body weight) should be given. If glucose fails to increase after 15 to 20 minutes, a repeat bolus should be administered. Higher concentrations of dextrose are not recommended as an initial bolus, as they frequently result in hyperglycemia with a subsequent insulin surge, triggering further hypoglycemia. (See "Primary drugs in pediatric resuscitation", section on 'Dextrose (glucose)'.)
•Dextrose infusion – After the initial bolus, a dextrose infusion should be started to prevent recurrent hypoglycemia. Infants should be started on a glucose infusion rate (GIR) of 5 to 6 mg/kg/minute (typically, dextrose 10% at maintenance rate). Older children have lower glucose requirements and can be initially placed on a GIR of 2 to 3 mg/kg/minute (typically, dextrose 5% at maintenance rate). The GIR should be increased every 15 to 20 minutes, in increments of 0.5 to 1 mg/kg/minute until the patient's plasma glucose concentration is at least 70 mg/dL.
GIR = (dextrose percentage × rate of infusion [mL/hr]) ÷ (6 × weight [kg])
Glucagon — If the child's mental status is altered and intravenous access cannot be obtained, glucagon can be used to acutely increase the plasma glucose. The recommended dose is 0.5 mg (<25 kg) or 1 mg (>25 kg) intramuscularly.
Glucagon is only effective for patients with suspected insulin-mediated hypoglycemia. This includes children with hyperinsulinism, surreptitious insulin administration, or sulfonylurea ingestion . Glucagon is not effective in other forms of hypoglycemia. This effect of glucagon is useful as a diagnostic tool. (See 'Diagnostic evaluation' below.)
Monitoring — The plasma glucose should be monitored every 15 to 20 minutes until it is >70 mg/dL (3.9 mmol/L). Thereafter, it can be checked hourly to ensure stability, and then subsequent checks can be further spaced to every three to four hours.
EVALUATION FOR THE CAUSE OF HYPOGLYCEMIA
Overview of the causes of hypoglycemia
The disorders of hypoglycemia can be categorized by their metabolic and hormonal profiles in response to fasting (see 'Glucose homeostasis in normal infants and children' above). This results in four broad categories of disorders (algorithm 1):
●Fatty acid oxidation disorders
●Ketotic hypoglycemic disorders
●Disorders of gluconeogenesis
History — The history of a child with hypoglycemia should include exploration of past medical history (including perinatal history), details of the acute event as well as any previous episodes, and family history.
●Age at presentation – Although there is considerable overlap, age at presentation suggests diagnostic categories:
•Neonatal period and early infancy – Hyperinsulinism, disorders of gluconeogenesis, most inborn errors of metabolism and panhypopituitarism
•First two years of life – Glycogen storage disorders, growth hormone or cortisol deficiencies
•Toddlers and young children – Ingestion, idiopathic ketotic hypoglycemia, glycogen storage disorders
•School-aged children and adolescents – Insulinoma, factitious hypoglycemia, other ingestions
●Symptoms – Although infants and young children with hypoglycemia are frequently asymptomatic, it is important to inquire about any symptoms of hypoglycemia prior to the acute event. (See 'Clinical features' above.)
●Triggers – The details of the acute event should be carefully explored and should include feeding history, concurrent illness, and medication exposure. This information helps to narrow the differential diagnosis of possible causes.
•Duration of fasting – Details should be obtained on how long the child fasted prior to the acute event, as well as how long the child fasts on a routine basis. A short duration of fasting (several hours) before onset of symptoms suggests hyperinsulinism or glycogen storage disorder type I or III. A longer duration of fasting (overnight) suggests a different glycogen storage disorder (types 0, VI, or IX), a hormone deficiency, a disorder of gluconeogenesis, or idiopathic ketotic hypoglycemia.
•Specific foods – Determine whether specific foods and nutrients may have triggered the hypoglycemic episode(s).
-Symptoms after ingestion of milk products or fructose may indicate galactosemia or hereditary fructose intolerance, respectively.
-Unripe lychee or ackee fruit (a staple in Jamaican diets) causes severe vomiting and hypoglycemia.
•Concurrent illness – In children with unrecognized hypoglycemic disorders, the episodes are often triggered by illnesses that interrupt normal feeding. Thus, further evaluation is indicated for a child presenting with hypoglycemia during a noncritical, intercurrent illness . The misperception that hypoglycemia is a common and normal result of routine childhood illnesses leads to delays in diagnosis and increased risk of neurologic damage. Hypoglycemia occurring during common childhood illnesses may be a clue to an underlying hypoglycemia disorder. For patients with critical illnesses, such as acute liver failure and sepsis, hypoglycemia is often a direct consequence of the illness rather than evidence of an underlying hypoglycemic disorder.
•Ingestion – The clinician must inquire about possible exposure to substances that cause hypoglycemia, such as oral hypoglycemic agents (sulfonylureas or meglitinides), ethanol, or beta blockers. (See "Causes of hypoglycemia in infants and children".)
●Past medical history
•Perinatal history – A thorough perinatal history is crucial and should include the birth weight, gestational age, and whether the child had hypoglycemia at birth or in the neonatal period, including what type of treatment was necessary. A history of being born large for gestational age suggests congenital hyperinsulinism or Beckwith-Wiedemann syndrome. Intrauterine growth restriction or born small for gestational age can result in the perinatal stress-induced form of hyperinsulinism .
Results of newborn screening tests should be reviewed. Important considerations include fatty acid oxidation disorders and galactosemia, in which hypoglycemia is a primary manifestation; these are included in most screening programs in the United States. Hypoglycemia may also be an associated feature in some other inborn errors of metabolism such as defects in amino acid metabolism. (See "Newborn screening", section on 'Implementation of screening'.)
•Prior events – It is important to explore the child's past medical history and to review available medical records to determine whether the child had other episodes suggestive of hypoglycemia that may have been missed or diagnosed as another condition (eg, seizure disorder).
●Family history – Family members with a history of hypoglycemia or a monogenic form of diabetes suggest the possibility of a familial hyperinsulinemic disorder. A family history of Reye syndrome, unexplained infant deaths, or unexplained hypoglycemic episodes suggest an inborn error of metabolism, particularly a fatty acid oxidation defect. The clinician should specifically inquire whether other family members have been diagnosed with any inborn error of metabolism (or "metabolic disorder").
●Physical examination – A thorough examination can provide important diagnostic clues.
•Anthropometrics – The child's weight and length or height should be measured and plotted on an appropriate growth chart, and the child's growth trajectory should be evaluated. Short stature or poor linear growth may indicate growth hormone deficiency or a glycogen storage disorder. Tall stature is associated with an overgrowth syndrome, such as Beckwith-Wiedemann syndrome or Sotos syndrome. Poor weight gain suggests a glycogen storage disease or a disorder of gluconeogenesis. Poor weight gain also may be caused by hypopituitarism and adrenocorticotropic hormone (ACTH) deficiency or primary adrenal insufficiency. Children who are underweight for age may also be at risk for idiopathic ketotic hypoglycemia.
•Midline defects (eg, a single central incisor, optic nerve hypoplasia, cleft lip or palate, umbilical hernia) and microphallus or undescended testicles in boys may indicate hypopituitarism and/or growth hormone deficiency.
•Hepatomegaly is common feature of the glycogen storage disorders.
•Macroglossia, abdominal wall defects, or hemihypertrophy may indicate Beckwith-Wiedemann syndrome .
•Hyperventilation may be a clue to metabolic acidosis from an inborn error of metabolism or ingestion.
•Hyperpigmentation suggests primary adrenal insufficiency.
Diagnostic evaluation — The history and physical examination are used to develop clinical suspicions, and the evaluation is tailored accordingly. As examples, clinical features suggesting an accidental or toxic ingestion or a specific inborn error of metabolism should prompt specific testing for the suspected disorder.
Critical samples — Evaluation for the majority of children presenting with hypoglycemia will require obtaining a "critical sample" of blood and urine at the time of hypoglycemia to measure metabolic fuels and counterregulatory hormones. These critical samples must be obtained at the time of hypoglycemia (plasma glucose <50 mg/dL) and before treatment, either during the initial acute episode or during a supervised diagnostic fast.
●Blood – The critical blood sample should be tested for:
•Comprehensive metabolic panel
•Free fatty acids (FFAs)
•Free and total carnitines
●Urine – The critical urine sample should be obtained at the same time and tested for organic acids. The sample should also be tested for ketones if blood BOHB testing is not available.
Diagnostic fast — If a critical sample is not obtained during a spontaneous episode of hypoglycemia, a diagnostic fasting test should be performed to determine the cause of the hypoglycemia .
For safety, the possibility of a fatty acid oxidation disorder should be excluded prior to performing the diagnostic fast, by measuring plasma carnitine and acyl-carnitine concentrations and confirming that these are normal before proceeding with the fast. Patients with fatty acid oxidation disorders may develop potentially life-threatening complications with prolonged fasting. (See "Causes of hypoglycemia in infants and children", section on 'Fatty acid oxidation disorders'.)
A diagnostic fast should only be performed in an inpatient setting with close supervision and adequate preparation. This preparation includes close review of the fasting protocol by the clinician and nursing staff and placement of an intravenous catheter for blood-drawing to obtain the critical sample.
●Start of test – The fast typically begins after dinner, bedtime snack, or evening feed.
●Monitoring – Obtain bedside glucose and BOHB every three hours while glucose is >70 mg/dL (3.9 mmol/L), hourly when glucose is 60 to 70 mg/dL (3.3 to 3.9 mmol/L), and every 30 minutes when glucose is 50 to 60 mg/dL (2.8 to 3.3 mmol/L).
●Endpoint of test – The test should be ended when any of the following conditions are met:
•Plasma glucose is <50 mg/dL (2.8 mmol/L), or
•Bedside plasma BOHB is >2.5 mmol/L, or
•The child develops symptoms of neuroglycopenia, or
•A specific duration has been reached. Durations used at the authors' institution: 18 hours if child is <1 month old, 24 hours if 1 to 12 months, 36 hours if >1 year, 48 hours for adolescents. Shorter durations may be considered based on clinical picture [18,19]
When any of these conditions are met, obtain the critical sample, perform a glucagon stimulation test if the plasma glucose is <50 mg/dL, as described below, and end the fast.
●Glucagon stimulation test – The glycemic response to glucagon provides an index of liver glycogen reserves. A glycemic response of ≥30 mg/dL is inappropriate, indicates excessive glycogen reserves, and provides indirect evidence of hyperinsulinism or insulin excess .
This test is performed when the glucose is <50 mg/dL (2.8 mmol/L). Then, 1 mg of glucagon is administered intravenously or subcutaneously, and then plasma glucose is monitored every 10 minutes for a maximum of 40 minutes.
•If the plasma glucose increases by <20 mg/dL (1.1 mmol/L) during the first 20 minutes following glucagon administration, the test should be terminated and the child fed.
•If the plasma glucose increases by ≥30 mg/dL (1.7 mmol/L) within 40 minutes after glucagon administration, this is considered an inappropriate glycemic response and is consistent with an insulin-mediated hypoglycemic disorder.
•If the plasma glucose increases by <30 mg/dL within 40 minutes after glucagon administration, an insulin-mediated hypoglycemic disorder is unlikely.
Interpretation of results — The results from the critical sample obtained during an episode of hypoglycemia (either at the time of initial presentation or during a diagnostic fasting test) and the glucagon stimulation test are used to identify the type of hypoglycemic disorder.
The disorders of hypoglycemia can be categorized by the levels of the metabolic fuels (lactate, ketones, FFAs) obtained at the time of hypoglycemia (algorithm 1). Other results from the critical sample further refine the diagnosis and/or direct additional testing.
Low ketones and low free fatty acids — Low ketones (BOHB) and low FFAs suggest an insulin-mediated hypoglycemic disorder. These disorders are also characterized by a positive glycemic response to glucagon and no acidosis (ie, bicarbonate is ≥18 mmol/L).
Insulin-mediated hypoglycemic disorders – The diagnosis of insulin-mediated hypoglycemic disorders, of which congenital hyperinsulinism is the most common, requires demonstrating evidence of insulin excess:
●Detectable insulin level at the time of hypoglycemia – When plasma glucose is <50 mg/dL (2.8 mmol/L), any detectable amount of insulin is abnormal. However, given the limitations and variable sensitivity of insulin assays, a detectable insulin level is not necessary to make the diagnosis of hyperinsulinism, and other criteria also need to be considered . Conversely, an undetectable insulin level does not rule out hyperinsulinism. The sensitivity and specificity of a detectable plasma insulin at the time of hypoglycemia are 82.2 and 100 percent, respectively . Similarly, a C-peptide concentration ≥0.5 ng/mL is evidence that insulin secretion is not appropriately suppressed in response to decreasing glucose concentrations. The sensitivity and specificity of a C-peptide plasma concentration of ≥0.5 ng/mL are 88.5 and 100 percent, respectively .
●Suppressed levels of BOHB and FFA – Insulin suppresses lipolysis and ketogenesis, resulting in inappropriately low levels of BOHB and FFA at the time of hypoglycemia. BOHB levels <1.8 mmol/L and FFA <1.7 mmol/L are consistent with insulin excess. A suppressed BOHB concentration of <1.8 mmol/L has a sensitivity and specificity of 100 percent . A suppressed plasma FFA concentration of <1.7 mmol/L has a sensitivity and specificity of 87 and 100 percent, respectively .
●Glycemic response to glucagon – A rise in glucose of more than 30 mg/dL after administration of glucagon is consistent with hyperinsulinemia because it reflects excessive insulin action on the liver. Insulin suppresses hepatic glycogenolysis, which leads to inappropriately high reserves of glycogen in the liver at the time of hypoglycemia. The sensitivity and specificity of a glycemic response ≥30 mg/dL to glucagon are 89 and 100 percent, respectively .
Insulin-mediated hypoglycemic disorders are listed in the table (table 4). The insulin level and C-peptide levels can help to distinguish some of these causes:
●Detectable insulin level with undetectable C-peptide – This combination suggests exogenous insulin administration (eg, due to surreptitious insulin administration in the case of medical child abuse). However, an undetectable insulin level does not exclude this possibility, because not all laboratory assays detect the insulin analogs; a special assay may be required to detect certain insulin analogs .
●Detectable insulin and C-peptide levels – This combination of findings is consistent with hyperinsulinism, sulfonylurea ingestion (accidental or deliberate), or insulinoma. In many cases, these causes can be distinguished by the patient's age and other historical features. If sulfonylurea ingestion is suspected, separate toxicology studies, including a specific screen for sulfonylureas, should be sent as soon as possible.
Low ketones and elevated free fatty acids — Fatty acid oxidation disorders are characterized by suppressed ketones with elevated FFAs, without acidosis (algorithm 1) . The plasma acyl-carnitine profile helps identify the specific type of disorder. (See "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)
Elevated ketones with acidemia — Elevated ketones and acidemia (bicarbonate <18 mmol/L) indicate a ketotic hypoglycemic disorder (table 4), which may be caused by several distinct mechanisms. Acidemia (serum TCO2 or bicarbonate <18 mmol/L) may not be present in some cases.
●Disorders of glycogen metabolism – The hepatic glycogen storage diseases (types 0, III, VI, and IX) are characterized by ketotic hypoglycemia (BOHB >2.5 mmol/L at the time of hypoglycemia), hyperlipidemia, and elevated liver function tests . Patients with glycogen storage disease type III will also have increased creatine kinase levels due to the involvement of muscle glycogen stores in this disorder, as well as hyperlipidemia.
●Hormone deficiencies – After the newborn period, patients with deficiencies of cortisol and growth hormone can present with ketotic hypoglycemia. However, in the neonate, hormone deficiencies or hypopituitarism will have laboratory findings identical to those found in hyperinsulinism (suppressed BOHB and FFA, glycemic response to glucagon). Low cortisol and growth hormone levels in the critical sample are not sufficient to diagnose adrenal insufficiency or growth hormone deficiency . If the critical sample has low cortisol or growth hormone concentrations, the appropriate stimulation testing must be obtained to confirm a diagnosis of the hormone deficiency prior to initiating treatment. A brain magnetic resonance imaging (MRI) should also be obtained if the diagnosis of growth hormone deficiency or hypopituitarism is made.
●Idiopathic ketotic hypoglycemia – This disorder is typically seen in toddlers presenting with a shortened fasting tolerance and marked ketosis (BOHB >2.5 mmol/L). This is a diagnosis of exclusion; other causes of ketotic hypoglycemia must be ruled out, including disorders of glycogen metabolism (glycogen storage diseases) and pituitary hormone deficiencies.
●Ketone utilization defects – Markedly elevated ketones with mild hypoglycemia may be seen in patients with ketone utilization defects. In contrast to other conditions that present with a pattern of ketotic hypoglycemia, in ketone utilization defects, hyperketonemia does not rapidly resolve after a feeding. These disorders are rare and result in elevated BOHB levels in both the fasting and fed state. 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).
Elevated lactate with acidemia — Elevated lactate levels with acidemia during an episode of hypoglycemia suggest a disorder of gluconeogenesis. These findings should prompt further testing for the specific disorder, such as glucose-6-phosphatase deficiency (glycogen storage disease type I) . Patients with these disorders will have elevations in their liver enzymes as well as increased levels of triglycerides and uric acid. Additionally, administration of glucagon following a meal results in increased lactate levels with no significant change in plasma glucose concentration. (See "Causes of hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis'.)
Additional testing — Once the general category of disorder is identified, further diagnostic testing can be performed to identify the specific disorder. A variety of disorders are diagnosed with genetic testing (eg, congenital hyperinsulinism, defects in gluconeogenesis or glycogenolysis, fatty acid oxidation disorders). Further information about identifying the specific disorder within each category is available in separate topic reviews. (See "Causes of hypoglycemia in infants and children".)
If the diagnosis and appropriate therapy cannot be readily determined, the child should be transferred to a center experienced with the diagnosis of hypoglycemic disorders. In these cases, whole-exome sequencing may be considered to identify new and previously unrecognized disorders.
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" and "Society guideline links: Hypoglycemia in the neonate".)
●Rapid overview – Hypoglycemia in infants and children requires prompt recognition, definitive diagnosis, and treatment to prevent permanent neurologic sequelae. The key steps are summarized in a rapid overview (table 3).
●Clinical features – Symptoms and signs of hypoglycemia include sweating, tremor, palpitations, pallor, tachycardia, weakness, and hunger (neurogenic symptoms), as well as lethargy, confusion, irritability, loss of consciousness, and seizure (neuroglycopenic symptoms). Older children and adults demonstrate the Whipple triad (symptoms consistent with hypoglycemia, low plasma glucose, and resolution of symptoms with normalization of plasma glucose). However, symptoms in infants and toddlers are frequently nonspecific and include irritability, lethargy, poor feeding, cyanosis, and tremor. Infants often manifest no symptoms of hypoglycemia until they present with a hypoglycemic seizure. (See 'Clinical features' above.)
●Definition – Hypoglycemia is defined clinically as a plasma glucose concentration low enough to cause signs and symptoms of brain dysfunction (neuroglycopenia). The threshold for confirming a diagnosis of hypoglycemia and for obtaining a diagnostic sample is <50 mg/dL (2.8 mmol/L), as documented by a laboratory-quality assay. (See 'Diagnosis of hypoglycemia' above.)
●Immediate management – Patients with confirmed or suspected hypoglycemia should be treated promptly by administering glucose. A sample of blood should be taken for diagnostic testing before administering the glucose, provided that it does not delay treatment. (See 'Glucose therapy' above.)
•Oral therapy – If the patient is fully conscious and able to drink and swallow safely, a rapidly absorbed carbohydrate (juice, glucose tablets, glucose gel) should be given by mouth. If the hypoglycemia does not improve within 10 to 15 minutes, parenteral glucose must be administered.
•Intravenous therapy – If the child is unconscious or not judged as safe to take oral carbohydrates, intravenous dextrose should be administered. An initial bolus of 2 mL/kg of dextrose 10% (ie, 0.2 g dextrose/kg body weight) should be given. After the initial bolus, a dextrose infusion should be started to prevent recurrent hypoglycemia (table 3). (See "Primary drugs in pediatric resuscitation", section on 'Dextrose (glucose)'.)
•Glucagon – In the child with altered mental status and without intravenous access, glucagon can be used to acutely increase the plasma glucose if insulin-mediated hypoglycemia is suspected. The recommended dose is 0.5 mg (for weight <25 kg) or 1 mg (for weight >25 kg) intramuscularly. (See 'Glucagon' above.)
●Evaluation for the cause of hypoglycemia
•Critical sample – Evaluation of hypoglycemia requires obtaining a "critical sample," which is a measurement of the hormones and fuels involved in glucose metabolism at the time of hypoglycemia (a plasma glucose <50 mg/dL). This sample can be obtained either during the initial acute episode, provided that it does not delay treatment, or during a supervised diagnostic fast. (See 'Critical samples' above.)
•Diagnostic fast – A diagnostic fast is performed in the inpatient setting, following a protocol that includes close monitoring to avoid severe hypoglycemia. For safety, the possibility of a fatty acid oxidation disorder should be excluded prior to performing the diagnostic fast. (See 'Diagnostic fast' above.)
The diagnostic fast typically includes a glucagon stimulation test. When the plasma glucose falls to <50 mg/dL, the critical sample is drawn, then glucagon is administered. A subsequent rise in plasma glucose ≥30 mg/dL indicates excessive glycogen reserves and provides indirect evidence of hyperinsulinism or insulin excess.
•Interpretation – The results from the critical sample obtained during an episode of hypoglycemia (either at the time of initial presentation or during a diagnostic fasting test) and the glucagon stimulation test are used to identify the type of hypoglycemic disorder (table 4). Hypoglycemic disorders can be categorized by the levels of the metabolic fuels (lactate, ketones, free fatty acids [FFAs]) in the critical sample obtained at the time of hypoglycemia (algorithm 1). Other results further refine the diagnosis and/or direct additional testing. (See 'Interpretation of results' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Agneta Sunehag, MD, PhD, and Morey W Haymond, MD, who contributed to an earlier version of this topic review.