Metabolic Disorders Associated With Neonatal Hypoglycemia

Stephen G. Kahler
Neoreviews 2004;5;e377
DOI: 10.1542/neo.5-9-e377

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Article

endocrinology

Metabolic Disorders Associated

With Neonatal Hypoglycemia
Stephen G. Kahler, MD*

Objectives

After completing this article, readers should be able to:

1. Describe four sources of glucose available to the neonate in the first 24 postnatal
hours.
2. Select the best routine diagnostic test to recognize fatty acid oxidation defects.
3. List three or more metabolic disorders that can be identified by newborn screening
performed using tandem mass spectrometry.

Introduction
Hypoglycemia is a common problem in neonates that has many causes. This review
focuses on metabolic disorders that may be associated with hypoglycemia in the
neonatal period.

Metabolic Requirements for Glucose Homeostasis in Newborns

During intrauterine life, the fetus derives fuel, as glucose, from the mother via the
placenta. After birth, the energy demands on the former fetus increase dramatically.
The baby now must maintain its own body temperature and must undertake the work
of breathing and other activities. Further, the maintenance of blood glucose levels
requires glycogenolysis and gluconeogenesis. Postnatally, there are four sources of
glucose: dietary glucose; glucose derived from the cleavage of more complex sugars in
the gut (eg, lactose to glucose and galactose); glucose released from glycogen stores
(primarily in the liver); and gluconeogenesis, in which glucose is synthesized from
carbon skeletons derived from certain amino acids using energy derived from catabolism of fatty acids.
Most term infants have sufficient glycogen stores to maintain blood glucose levels for
several hours before gluconeogenesis is required. Infants who are breastfed in the
United States typically are offered only water as a supplement to human milk during
the first few postnatal days, a period when the mothers milk supply is not yet
established. In contrast, formula-fed babies receive calories by mouth by the end of the
first postnatal day. Consequently, the metabolic stress of prolonged fasting occurs
more frequently in breastfed than in formula-fed babies. Although breastfed babies
have higher levels of ketone bodies that appear to provide adequate energy during this
high metabolic stress period, they may be more vulnerable to metabolic disorders that
limit ketone production.

Hypoglycemia
Hypoglycemia is defined on the basis of symptoms and blood glucose levels. Most
authorities regard a blood glucose level below 40 mg/dL (2.3 mmol/L) as low, regardless
of the presence of clinical signs. (Blood glucose concentrations may be transiently lower in
the first hours after birth.) Some infants exhibit clinical findings (eg, jitteriness, lethargy) at
higher levels that respond immediately to glucose, suggesting that their blood glucose
concentrations were too low for adequate function. Some of the symptoms of hypoglycemia (eg, lethargy) are due to lack of glucose; others (eg, jitteriness) are due to the
hormonal response to hypoglycemia (especially increased catecholamine release). Apnea or
seizures may occur, and there may be cardiac dysfunction.
*Visiting Professor of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of
Medicine, Baltimore, Md.
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endocrinology neonatal hypoglycemia

Metabolic Disorders Presenting With

Hypoglycemia
The disorders discussed in this article are presented in
order based on the glucose source affected (ie, digestion
and absorption, glycogenolysis, and gluconeogenesis).

Disorders of Absorption and Digestion

Disorders of absorption or digestion rarely are encountered in newborns; if they are present (as in lactose
intolerance), they rarely are sufficiently severe to result in
hypoglycemia. However, they typically cause significant
diarrhea.
Hepatocellular dysfunction from any cause may lead
to hypoglycemia; the liver dysfunction should be obvious
if there is jaundice. Infection and galactosemia are common causes. Galactosemia due to galactose-1-uridyl
phosphate uridyltransferase deficiency commonly causes
hepatic dysfunction, but may not cause marked hypoglycemia. Its diagnosis in the newborn period is critical
because of the associated liver and renal dysfunction,
cerebral edema, and cataracts and the risk of gramnegative sepsis. When suspected, all intake of galactose
(human milk and cow milk formulas) must cease. The
diagnosis can be suspected on the basis of positive reducing substances in the urine and confirmed by metabolite
or enzyme assay. Urine obtained more than 1 day after
cessation of galactose intake may be negative for reducing substances. Tyrosinemia may cause a similar picture
of hepatocellular and renal dysfunction. Fructose intolerance appears similarly, but infants usually are not exposed to fructose or sucrose.

Disorders of Glycogenolysis
The first glycogen storage disease discovered, von Gierke
disease (GSD 1) is a defect of glucose release from
hepatic cells due to abnormalities of glucose-6phosphatase. Several subcategories exist. GSD 1 actually
is a mixed disorder because glucose-6-phosphate, the
substrate for the abnormal enzyme, is derived from both
glycogen breakdown and gluconeogenesis. The result of
the enzymatic defect is hypoglycemia as soon as intestinal
sources of glucose are exhausted (typically 2 h after a
feeding) and production of alternate fuelslactate and
ketone bodies begins. It is not uncommon for an infant
who has GSD 1 to have a blood glucose level of
20 mg/dL (1.1 mmol/L) and minimal symptoms due to
the presence of alternate substrates.
The other major defects of glycogenolysis are deficiencies of glycogen debrancher enzyme, liver phosphorylase, and the phosphorylase kinase system. These conditions usually are silent in the newborn period because

prolonged fasting is rare. Fasting hypoglycemia without

acidosis occurs after several hours. Hepatomegaly occurs
within a few months and consists of both increased
glycogen and fat. (Splenomegaly rarely is found in glycogen storage disorders, which is an important differential point.) Disorders due to impaired glycogen synthesis
include brancher deficiency, which causes cirrhosis and
may cause cardiomyopathy, and the very rare glycogen
synthase deficiency (GSD type 0).

Disorders of Gluconeogenesis
The fasting that accompanies the first few days of breastfeeding is a major test of gluconeogenesis. Accordingly,
defects that impair gluconeogenesis may result in significant and catastrophic decompensation. Disorders due to
impaired fatty acid oxidation can result in hypoglycemia,
with the added problem of the accumulation of toxic
intermediates. The most common disorder of fatty acid
oxidation is medium-chain acyl CoA dehydrogenase
(MCAD) deficiency, which occurs in perhaps 1 in
10,000 people of northern European descent. A few
percent of MCAD-deficient infants, especially breastfed
ones, experience an episode of hypoglycemia in the first
few postnatal days. However, most affected infants do
not have symptoms until a few months of age or even
later. Decompensations often are provoked by infection
in conjunction with fasting and may be exacerbated by
carnitine depletion. The response to intravenous administration of glucose may be slow, with the blood
glucose concentration rising but the lethargy persisting,
which reflects the toxicity of accumulated metabolic
intermediates.
Other disorders of fatty acid oxidation that may
present in the newborn period are the defects of longchain fatty acid oxidation. Cardiomyopathy, encephalopathy, and hepatic dysfunction may be prominent in deficiencies of very-long-chain acyl CoA dehydrogenase,
long-chain hydroxyacyl CoA dehydrogenase (LCHAD),
carnitine-acylcarnitine translocase, and carnitine palmitoyltransferases I and II. LCHAD deficiency in the fetus
can provoke significant liver dysfunction (HELLP syndrome, acute fatty liver of pregnancy) in the heterozygous mother, although most cases of these maternal
conditions are unrelated to LCHAD deficiency.
Mild hypoglycemia certainly can occur in various organic acidurias (eg, propionic and methylmalonic acidemia, maple syrup urine disease), but the presenting
urgent problems in these disorders most commonly are
ketoacidosis, lactic acidosis, and hyperammonemia, with
associated encephalopathy. Other causes of hepatocellular dysfunction also can lead to hypoglycemia, but the

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endocrinology neonatal hypoglycemia

diagnosis in such cases generally is evident because of the

presence of laboratory values suggestive of liver failure.
Hyperinsulinism is a metabolic disorder that affects
both glycogenolysis and gluconeogenesis and most commonly reflects the presence of maternal hyperglycemia.
Other causes are fetal overgrowth syndromes, especially
Beckwith-Wiedemann syndrome, and overgrowth of the
pancreas, previously referred to as nesidioblastosis. (See
Genetic and Nongenetic Forms of Hyperinsulinism in
Neonates in this issue.)
Other hormones involved in glucose regulation include glucagon, cortisol, growth hormone, thyroid hormone, and catecholamines. Deficiencies of any of these
hormones from structural or functional defects may be
associated with neonatal hypoglycemia. Growth hormone deficiency may be silent in the newborn period
because insulin is a more important growth hormone in
the fetus. Cortisol deficiency (as occurs in congenital
adrenal hyperplasia) also may be cryptic initially, but
it may present with subsequent complete metabolic
collapse later in the first 2 postnatal weeks, with accompanying salt-wasting, hypoglycemia, and circulatory
collapse.
The congenital disorders of glycosylation (CDGs)
(formerly carbohydrate-deficient glycoprotein disorders)
form a new category of disorders that lead to impaired
synthesis of many molecules, including hormone and
lipid carriers. Hypoglycemia often occurs, and plasma
cholesterol also may be very low in these conditions.
Deficient steroid-binding protein leads to functional cortisol deficiency, while (pseudo)hypothyroidism may be
detected by newborn screening because of low thyroidbinding globulin. CDG 1a, which is due to phosphomannomutase 2 deficiency, has accompanying malformations, including cerebellar hypoplasia. CDG 1b, with
an associated defect in phosphomannose isomerase, may
present with hypoglycemia followed by protein-losing
enteropathy and hepatic fibrosis. This condition is
treated successfully with oral mannose. Many other
CDGs are known. All are recognized by isoelectric focusing of transferrin.

Identification of the Infant Who Has a

Metabolic Disorder
The pregnancy and history of feeding and fasting can
point to likely causes of hypoglycemia. Investigation of
hypoglycemia includes the family history, pregnancy history (with particular reference to weight gain and glucose
tolerance), peculiarities regarding labor and delivery,
examination of the placenta (not always done), and examination of the infant. Common causes of neonatal

hypoglycemia, such as sepsis, intrauterine growth restriction, and transient hyperinsulinism, must be ruled out
before more unusual diagnoses are entertained. The
feeding history and risk factors for infection are especially
important. Overgrowth or intrauterine starvation is obvious. Prenatal infection can cause placental insufficiency, leading to intrauterine starvation with subsequent hypoglycemia and hepatic dysfunction, which can
exacerbate abnormalities of glucose homeostasis.
Essentially all of the metabolic disorders discussed in
this article are inherited in an autosomal recessive pattern. The family history may be positive for similarly
affected siblings or unexplained infant deaths. Consanguinity usually is not present, but can suggest the presence of a metabolic disorder that has a recessive inheritance when it is. Genital abnormalities (eg, virilization,
hyperpigmentation) can point to adrenal hyperplasia.
Midline facial defects may suggest abnormalities of pituitary function. MCAD deficiency is characterized by
acute illness, not chronic problems. In contrast, infants
who have organic acidurias may experience chronic feeding difficulties, but may not have complete metabolic
collapse until after the first several days to a few weeks
after birth. An increasing number of metabolic disorders,
including some discussed here, can be identified on the
initial routine newborn screen.

Diagnostic Tests
A blood sample obtained just before glucose is administered can provide invaluable information later, so it
should be obtained if at all possible. This sample offers
convincing information regarding insulin and other hormones, which changes rapidly after glucose is administered. The blood glucose test strip, based on glucose
oxidase, is a rapid but not always reliable test at low levels,
so abnormalities must be confirmed with a proper blood
glucose determination. Samples for insulin, cortisol,
growth and thyroid hormones, electrolytes, ammonia,
amino acids, carnitine and acylcarnitines, blood culture,
blood counts, and liver function/transaminases address
most of the potential causes, but not all of these tests are
needed in a given situation.
Measurement of blood electrolytes, with calculation
of the anion gap, can suggest acidosis and the presence of
a missing anion (usually lactate or ketone bodies). The
arterial pH may be normal, even in the presence of
significant acidosis, because of respiratory compensation.
If acidosis is suspected, lactate should be measured directly. Other blood tests should include measurement of
insulin and other hormones (growth hormone, thyroid
hormone, cortisol) and plasma amino acid analysis. SpeNeoReviews Vol.5 No.9 September 2004 e379

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endocrinology neonatal hypoglycemia

cial attention should be paid to alanine (which reflects

elevation of pyruvate and lactate) and the gluconeogenic
amino acids. Analysis of blood spot acylcarnitines can
reveal MCAD deficiency or other disorders of fatty acid
oxidation rapidly.
Urinalysis should be performed in all cases of suspected metabolic disorders, although the clinician
should remember that the dipstick does not discriminate
between the various reducing sugars. The dipstick also
does not detect beta-hydroxybutyrate, a ketone body.
Measurement of urine organic acids can reveal excessive
lactate, ketone bodies, and the metabolites of organic
acidurias and fatty acid oxidation defects. The acylcarnitine profile generally is abnormal in the presence of fatty
acid oxidation defects, but infants who have organic
acidurias may have normal organic acid levels between
episodes of acute decompensation. A fasting stress test
may be necessary to reveal a deficient hormonal response
to hypoglycemia. Because such a test can be dangerous in
MCAD deficiency and fatty acid oxidation defects, it
should be undertaken only after these disorders have
been ruled out by acylcarnitine analysis.

Newborn Screening
The introduction of tandem mass spectrometry for newborn screening is leading to early diagnosis of many
life-threatening disorders. At least 30 state newborn
screening programs in the United States have adopted or
are evaluating this technique, and two private laboratories also are offering it. The technology allows the separation of complex mixtures (extracts of dried blood
spots) and identification of components of interest in
about 2 minutes. (In comparison, urine organic acid
analysis by gas chromatography-mass spectrometry can
take 40 min per sample after sample preparation; quantitative amino acid analysis by column chromatography
can take a few hours per sample.) The technique is
conceptually simple: mass spectrometers weigh molecules (ie, determine their mass). Two mass spectrometers
coupled in series, therefore, can determine the mass of a
parent molecule and fragments derived from the parent.
The addition of acylcarnitine profiling to newborn
screening panels allows the identification of nearly all
children who have the various fatty acid oxidation defects. Acylcarnitines share a common core and differ in
their side chains, which have different masses. More than
a dozen different disorders of fatty acid and organic acid
metabolism can be distinguished rapidly by the different
acylcarnitines that accumulate because of impaired enzyme activity (eg, various acyl-CoA dehydrogenase defi-

ciencies). Many different amino acids also can be determined in the same instrument at the same time, leading
to rapid diagnosis of more than a dozen aminoacidopathies, such as phenylketonuria, tyrosinemia, and maple
syrup urine disease. The technique also can be used to
identify infants who have many disorders of organic acid
and urea cycle metabolism.
Batched, semiautomated preparation of samples
makes it possible to analyze several hundred samples per
day on a single instrument. Testing usually is performed
on a sample obtained between 48 and 72 hours of age.
The sample must be dried, shipped to the screening
laboratory, and analyzed. Thus, the infant may be nearly
1 week old before the results are known. During this
interval, the disorders that are provoked by fasting in the
newborn period, especially MCAD deficiency, already
may have presented clinically.
In some cases, the newborn screening test provides a
definitive diagnosis; in others, the abnormality may be
subtle, requiring repeat testing or different tests. A normal newborn screening result cannot rule out a particular
disorder completely, so sick infants or children in whom
metabolic disease is suspected should be evaluated as if
newborn screening had not been performed.

Conclusion
Although rare, metabolic disorders can lead to significant
morbidity and mortality due to severe hypoglycemia and
metabolic collapse. Breastfed infants may be at increased
risk, particularly from disorders of ketogenesis, during
the first 48 hours of postnatal life. Fortunately, improved
techniques for newborn screening can help to identify
many affected infants before they present clinically.

Suggested Reading
Burton BK. Inborn errors of metabolism in infancy: a guide to
diagnosis. Pediatrics. 1998;102:e69 77. Available at: http://
pediatrics.aappublicationsorg/cgi/content/full/102/6/e69
Hoffman GF, Nyhan WL, Zschocke J, Kahler SG, Mayatepek E.
Inherited Metabolic Diseases. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001
Ogier de Baulny H. Management and emergency treatments of
neonates with a suspicion of inborn errors of metabolism. Semin
Neonatol. 2002;7:1726
Ozand PT. Hypoglycemia in association with various organic and
amino acid disorders. Semin Perinatol. 2000;24:172193
Pitt JJ, Eggington M, Kahler SG. Comprehensive screening of urine
samples for inborn errors of metabolism by electrospray tandem
mass spectrometry. Clin Chem. 2002;48:1970 1980
Roe CR. Inherited disorders of mitochondrial fatty acid oxidation:
a new responsibility for the neonatologist. Semin Neonatol.
2002;7:37 47

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endocrinology neonatal hypoglycemia

NeoReviews Quiz
5. The occurrence of hypoglycemia as a manifestation of a metabolic disorder varies in relation to the
postnatal age of the infant. Of the following, symptomatic hypoglycemia occurring soon after birth is most
likely to be the presenting feature of:
A.
B.
C.
D.
E.

Galactosemia.
Glycogen debrancher enzyme deficiency.
Maple syrup urine disease.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
Methylmalonic acidemia.

NeoReviews Vol.5 No.9 September 2004 e381

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Metabolic Disorders Associated With Neonatal Hypoglycemia

Stephen G. Kahler
Neoreviews 2004;5;e377
DOI: 10.1542/neo.5-9-e377

Updated Information &

Services

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