Basics
Description
- Hypoglycemia is a frequent finding in the neonatal period, which results from the imbalance between carbohydrate intake, endogenous glucose production, and tissue usage.
- Neonates stabilize their serum glucose levels by about 12 hours after birth to 45 mg/dL (2.6 mmol/L). In a healthy state, glucose homeostasis underlays tight regulation through glucose-lowering hormones (insulin) and counterregulatory, glucose-mobilizing hormones (cortisol, growth hormone, and others) by acting on glycolysis, gluconeogenesis, glycogenolysis, and many other metabolic pathways involved in the biosynthesis, catabolism, or transport of carbohydrates, lipids, and amino acids.
- Hence, many inborn errors of metabolism can present with episodes of hypoglycemia during metabolic crises, which can be life threatening if not treated promptly.
- First presentation of an inborn error of metabolism can be at any age, with most cases presenting during times of metabolic stress or transition, as in infancy, illness, and dietary changes. Therefore, it is prudent to quickly establish a tentative diagnosis and initiate treatment in a sick neonate.
Epidemiology
- Incidence of hypoglycemia is estimated at 1 " 3/1,000 live births.
- Incidence of inherited forms is estimated at 1/50,000 live births in sporadic populations and higher in Ashkenazi Jews.
- The incidence of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency ranges from 1:4,900 to 1:17,000 live births.
- Incidence of familial hyperinsulinism is 1 in 2,500 live births.
Genetics
Almost all inborn errors of metabolism causing hypoglycemia are autosomal recessive. Congenital hyperinsulinism can be autosomal dominant or recessive. Glycerolkinase deficiency is X-linked.
Pathophysiology
- Through glycolysis and oxidative phosphorylation, glucose is a major source of cellular energy (ATP). Failure to produce ATP is probably the main source of hypoglycemia-associated tissue dysfunction.
- The brain preferentially uses glucose metabolism to produce energy and is particularly sensitive to hypoglycemia.
- A long list of metabolic disturbances in a variety of pathways can result in hypoglycemia.
- Neonates are at particular risk for hypoglycemia because they use glucose more rapidly than adults and have immature ability to obtain energy from other sources (glycogen, muscle protein, adipose tissue).
Etiology
- Inherited defects in biochemical pathways affecting metabolism of fats, amino acids, or carbohydrates
- Mutations in genes known to be involved in glucose metabolism, for example, congenital hyperinsulinism (ABCC8, KCNJ11, GLUD1, CAK, HADH, SLC16A1, HNF4A) and Fanconi-Bickel syndrome (GLUT2, SCLA2)
Diagnosis
History
- Family history: Because inborn errors of metabolism are genetic disorders, patients may have a family history of poorly explained pediatric death. Diagnoses to ask about include the following:
- Sepsis (was an organism identified?)
- Sudden infant death syndrome
- Cardiomyopathy
- Uncontrollable seizures
- Coma
- Liver failure
- Unexplained developmental delay or hypoglycemia in older siblings
- First hypoglycemia after introducing different foods (e.g., milk, fruits, etc.)
- Complications with the pregnancy:
- Maternal diabetes
- Certain disorders of fatty acid oxidation are associated with fatty liver of pregnancy or HELLP (hypertension, elevated liver enzymes, low platelets) syndrome.
- Small for gestational age/intrauterine growth retardation/prematurity: may present with transient hypoglycemia
- Results of newborn screen: Children are tested for a variety of inborn errors of metabolism through newborn screening programs. Some of these disorders predispose to hypoglycemia and have specific therapies.
- Current diet and feeding schedule: Timing of hypoglycemia helps form differential diagnosis:
- Hypoglycemia occurring shortly after feeding (0 " 4 hours) is suggestive of hyperinsulinism or inability to process carbohydrates (hereditary fructose intolerance).
- Hypoglycemia between 2 and 10 hours after feeding is concerning for glycogen storage diseases, defects in gluconeogenesis, or counterregulatory hormone deficiencies.
- Hypoglycemia after fasting (>6 hours) is suggestive of ketotic hypoglycemia, defects in gluconeogenesis, or fatty acid oxidation defects.
Physical Exam
- ABCs and vital signs: Tachycardia, irritability, and weakness are commonly seen in hypoglycemia.
- Facies: Decreased interpupillary diameter or other midline anomalies occur in association with abnormalities of the pituitary.
- Skin: Diaphoresis is an effect of the catecholamine surge that accompanies hypoglycemia.
- CVS: cardiomyopathy (fatty acid oxidation defects, glycogen storage disorders, organic acidemias)
- Respiratory: Tachypnea may be the result of either respiratory compensation of metabolic acidosis or hyperammonemia.
- Hepatomegaly
- Occurs in many inborn errors of metabolism causing hypoglycemia and is a key feature in differentiating possible diagnoses.
- May be due to abnormal accumulation of lipid (e.g., in fatty acid oxidation defects) or glycogen (e.g., glycogen storage disease).
- Renal: nephropathy/tubulopathy (organic acidemias, Fanconi-Bickel syndrome)
- GU:
- Virilization in congenital adrenal hyperplasia
- Micropenis in hypopituitarism
- Neurologic: Every neonate with a suspected inborn error of metabolism needs a complete neurologic exam to evaluate for level of consciousness, tone, unusual movements, and reflexes. Symptoms of neuroglycopenia include the following:
- Tremulousness
- Polyphagia
- Seizures
- Irritability
- Weakness
- Hypotonia
- Stupor and coma occur if hypoglycemia is not reversed
- Growth parameters:
- Infants with Beckwith-Wiedemann syndrome, familial hyperinsulinism, or infants of diabetic mothers may be large for gestational age.
- Beckwith-Wiedemann syndrome may also present with additional physical stigmata (hemihypertrophy, visceromegaly, macroglossia, abdominal wall defects) and hyperinsulinism.
Diagnostic Tests & Interpretation
Lab
The goal of the initial lab evaluation is to make a presumptive diagnosis. In many cases, definitive diagnosis requires specialized and time-consuming tests.
- Initial labs for a presumptive diagnosis in patient with hypoglycemia:
- Dextrose stick
- Urine dipstick: glucosuria (glucose transporter defects)
- Electrolytes, BUN, creatinine, anion gap
- CBC, blood culture
- Serum and urinary ketones
- Arterial blood gas with lactate
- Liver function tests and PT/PTT
- Urinalysis for reducing substances: positive in fructose intolerance, galactosemia
- Plasma ammonia levels (obtained as free-flowing samples without tourniquet): Sample must be placed on wet ice and immediately transported to the lab for processing.
- Review state newborn screen.
- Suspected disorders and follow-up testing:
- Familial hyperinsulinism: high insulin levels, low/absent serum/urinary ketones
- Adrenal insufficiency, hypopituitarism: low cortisol, growth hormone, epinephrine/norepinephrine levels
- Defects of fatty acid oxidation or ketogenesis: plasma acylcarnitine profile, free fatty acids+ 3-hydroxybutyrate/ketones (low)
- Organic acidemias: urine organic acids, acylcarnitine profile
- Factitious hypoglycemia/Munchausen syndrome by proxy: elevated C-peptide levels, toxicology screen: sulfonylureas, ethanol
- Urea cycle defects: plasma amino acids, urine orotic acid
- Galactosemia: urine galactitol, red blood cell galactose-1-phosphate, uridyltransferase (GALT) activity, total galactose
- Defects of gluconeogenesis/glycogen storage disease: arterial blood gas with lactate (lactic acidosis), +/ ¢ elevated creatine kinase (CK), specific enzyme testing or mutation analysis
- Prolonged fasting: elevated free fatty acids+ 3-hydroxybutyrate
- Gene testing for specific disorders (Beckwith-Wiedemann syndrome)
Differential Diagnosis
Hypoglycemia is caused by increased glucose use or decreased glucose availability. Examples of disorders causing each:
- Increased glucose use
- Sepsis increases metabolic demand and is a leading cause of neonatal hypoglycemia.
- Familial hyperinsulinism: suspect when required glucose infusion rate (GIR) >10 " 20 mg/kg/min to maintain normoglycemia
- Increased insulin production: Beckwith-Wiedemann syndrome
- Decreased insulin counterregulatory hormones (glucagon, cortisol, growth hormone) due to adrenal insufficiency, hypopituitarism
- Decreased glucose availability/production
- Infants of diabetic mothers
- Small for gestational age: low energy stores, immaturity of glucose-regulating pathways
- Liver failure/disease from ingested carbohydrates: galactosemia, hereditary fructose intolerance
- Glycogen storage diseases
- Glycerol kinase deficiency, glycerol intolerance
- Decreased gluconeogenesis: phosphoenolpyruvate carboxykinase deficiency, fructose-1, 6-diphosphatase deficiency, pyruvate carboxylase deficiency
- From decreased efficiency of pathways providing alternate energy sources: organic acidemias, fatty acid oxidation defects
- Disorders of glucose transporter:
- GLUT1 or 2 deficiency
- SGLT1 or 2 deficiency
- Various toxins or medications interfere with pathways needed to maintain glucose homeostasis, including salicylates, valproate, ² blockers, ethanol, and exogenous insulin.
Treatment
Presumptive treatment should not await a definitive diagnosis but should be based on clinical suspicion and initial labs.
General Measures
- A well-appearing neonate with a low dextrose stick should be fed immediately. If feeds are contraindicated or not tolerated, obtain IV access.
- In children with associated physical or laboratory findings consistent with an inborn error of metabolism or other serious illness (e.g., vital sign instability, lethargy, acidosis), IV access should be obtained.
- A dextrose bolus (e.g., 5 cc/kg D10) rapidly corrects hypoglycemia in most cases. Infants requiring high glucose infusion rates to maintain normoglycemia are suspicious for hyperinsulinism.
Additional Therapies
Specific therapies vary according to the diagnosis and are best carried out by metabolic specialists:
- Hyperinsulinism
- May require continuous glucose administration of 7 " 10 mg/kg/min (IV or via continuous gastric feeds)
- Medical therapies including diazoxide and octreotide
- Pancreatectomy
- Deficiencies in counterregulatory hormones: hormone supplementation
- Galactosemia, hereditary fructose intolerance: Eliminate offending agent from diet.
- Fatty acid oxidation disorders, glycogen storage disease type I, defects in gluconeogenesis: frequent feeds, fasting avoidance, increase caloric intake during stress. Some children may benefit from cornstarch supplementation before bedtime to prevent nocturnal hypoglycemia.
Ongoing Care
Complications
Recurrent and severe hypoglycemic episodes affect neurocognitive development.
Additional Reading
- Datye KA, Bremer AA. Endocrine disorders in the neonatal period. Pediatr Ann. 2013;42(5):67 " 73. [View Abstract]
- Hoe FM. Hypoglycemia in infants and children. Adv Pediatr. 2008;55:367 " 384. [View Abstract]
- Stanley CA. Hypoglycemia in the neonate. Pediatr Endocrinol Rev. 2006;4(Suppl 1):76 " 81. [View Abstract]
Codes
ICD09
- 775.6 Neonatal hypoglycemia
- 277.9 Unspecified disorder of metabolism
- 277.85 Disorders of fatty acid oxidation
- 270.0 Disturbances of amino-acid transport
ICD10
- P70.4 Other neonatal hypoglycemia
- E88.9 Metabolic disorder, unspecified
- E88.89 Other specified metabolic disorders
- E72.09 Other disorders of amino-acid transport
SNOMED
- 52767006 Neonatal hypoglycemia (disorder)
- 75934005 Metabolic disease (disorder)
- 128596003 Medium-chain acyl-coenzyme A dehydrogenase deficiency (disorder)
- 61598006 Glycogenosis with glucoaminophosphaturia (disorder)
FAQ
- Q: Why is hypoglycemia dangerous?
- A: Glucose is a crucial source of rapidly available energy for many tissues, especially the brain. Prolonged hypoglycemia causes CNS damage.
- Q: Why are the critical labs so important?
- A: In some metabolic disorders, the biochemical disturbance is apparent only during hypoglycemic episodes. Collecting this panel of informative labs during an episode greatly increases the chance of making a diagnosis.
- Q: If an infant dies before a diagnosis is made, what can be done to provide information for family members regarding future pregnancies?
- A: A postmortem exam can be helpful. A skin biopsy can yield fibroblasts for genetic and biochemical assays to investigate defects in specific pathways, and a muscle biopsy can be used to investigate mitochondrial disorders. Follow specific protocol for obtaining biopsies.