SYMPOSIUM: DIABETES MELLITUS
Tabitha L Randell MBChBFRCPCH is Consultant in Paediatric Endocrinology
Diagnosis and management
of hypoglycaemia beyond the
neonatal period
Tabitha L Randell
Abstract
Hypoglycaemia in childhood beyond the neonatal period is a relatively
common problem and is defined as a plasma glucose level of less than 2.8
mmol/litre. If it is not recognized and treated promptly, it can lead to
significant morbidity and mortality. Hypoglycaemia has many and varied
causes, including endocrine disorders, inborn errors of metabolism,
poisoning, severe infections and ketotic hypoglycaemia (which should be a
diagnosis of exclusion). When possible, blood and urine samples to
determine the cause of hypoglycaemia should be taken before treatment is
instigated, as some abnormalities are unmasked only during the episode of
low blood sugar. Once the causehasbeen identified,treatment may involve
avoidance of prolonged fasting, dietary manipulation, medication or even
surgery.
Keywords childhood; diagnosis; hypoglycaemia; management
Introduction
Hypoglycaemia is a common problem in infancy and childhood.
Immediately after birth, the body undergoes dramatic changes to adapt to
the extra-uterine environment and hypoglycaemia is a normal part of this.
It is thought that the decline in glucose is necessary to allow enzyme
activation by the hormonal surges that low glucose levels induce. This
review is concerned with hypoglycaemia beyond the neonatal period;
thus, immediate post-natal adaptations are not covered in any detail, and
neonatal hypoglycaemia is specifically excluded from the discussion.
Atbirth,theneonateisplungedfromastateofglucosesufficiency (via the
placenta) to sudden starvation. During the first few hours
afterbirth,bloodglucoseinnormalhealthyneonatesdecreasesfrom close to
maternal levels to about 2.5 mmol/litre. This results in a series of
dramatic adaptations that trigger gluconeogenesis, the releaseoffree fatty
acidsand the production of ketone bodies. Once this transition is
complete, however, the mechanisms of glucose homeostasis are similar
throughout infancy, childhood and
adulthood.Themajordifferencebetweenadultsandchildrenistherateof
glucose utilization and the susceptibility of the developing brain to the
adverse effects of hypoglycaemia.
Maintenance of normal blood glucose levels involves a complex
interplay of hormones such as insulin, glucagon, adrenaline, growth
hormone and cortisol with plasma glucose concentration. If there is
equilibrium between glucose production and glucose utilization, blood
sugar levels are normal. Hypoglycaemia occurs when more glucose is
being used than can be
PAEDIATRICS AND CHILD HEALTH 23:4
and Diabetes, Nottingham University Hospitals NHS Trust, Nottingham,
UK. Conflict of interest: none.
What’s new?
C
PETscanning to differentiate between focal and diffuse CHI is now
available intheUK(previously requiredtraveltocentresinEurope)
C
Raised blood ketone levels on near patient testing can be a helpful
in excluding hyperinsulinism as a cause of hypoglycaemia
C
MCADD testing has been part of the newborn screening programme
in the UK since 2009
produced, and this can happen for numerous reasons, including endocrine
abnormalities, inborn errors of metabolism, idiopathic ketotic
hypoglycaemia, severe infections and drugs (accidental and otherwise).
If it is not recognized and treated promptly, hypoglycaemia can have
severe neurological consequences, particularly in infants and very young
children. It is also important to discover the underlying cause of the
hypoglycaemia, so that appropriate treatment can be instigated to prevent
recurrence and risk of further morbidity and mortality.
Definition
Hypoglycaemia is both a biochemical and a functional concept. It is
difficult to find a consensus even on the biochemical definition of
hypoglycaemia, with three different textbooks giving three different
values for the concentration of plasma blood glucose that should be
considered hypoglycaemia beyond the neonatal period (2.2e2.8
mmol/litre). There is frequently a poor correlation between plasma
glucose concentration and symptoms, and there has been much debate
about the risk of long-term sequelae relative to the severity and duration
of the hypoglycaemic episode. In this review, hypoglycaemia is
considered to be a plasma glucose concentration of less than 2.8
mmol/litre. Whole blood glucose levels tend to be 10e15% lower.
Mechanisms of glucose homeostasis
The normal response of the body to declining blood glucose is to switch
off insulin production and trigger release of glucagon and other counter-
regulatory hormones. This in turn leads to the release of glucose by the
conversion of glycogen to glucose by
glycogenolysisintheliver,andtheconversionofproteintoglucose by
gluconeogenesis. Gluconeogenesis is accelerated by cortisol. Lipolysis
also occurs, leading to the release of glycerol and free fatty acids (FFAs).
These are transported into the liver
mitochondria,wheretheFFAsareoxidizedtoproduceketonebodiesandthe
glycerolisconvertedtoglucosebygluconeogenesis.Ketonebodies are used
as an alternative energy source, which is particularly important for the
brain as it has no other substantial non-
glucosederivedenergysource.Theseresponsesallowthebodytocontinue to
function, conserving glucose for tissues such as red-blood cells that are
entirely reliant on it as a fuel source.
Young children have limited glycogen stores, lasting for a maximum
of 12 hours, while infants often have sufficient stores for only 4 hours.
After that time, the body becomes dependent on protein and fat for its
fuel sources. Ketosis and ketonuria occur in children after only a few
hours of fasting. Children have higher glucose requirement rates than
adults because their brain to body size ratio is much larger and the brain
152 2013 Published by Elsevier Ltd.
 SYMPOSIUM: DIABETES MELLITUS

is the body’s main consumer of glucose. Adult brains also appear to adapt
much better to the use of ketone bodies as a fuel source than do children’s
brains, as measured by the effect on cognitive function. These last two
factors help to explain why children are much more vulnerable to the
effects of hypoglycaemia than adults.

β β β
Symptoms of hypoglycaemia
The mechanisms described above usually allow the body to maintain
glucose levels at an adequate level until eating or drinking replenishes
supplies. Sometimes, however, stressors on the body are such that
glucose levels decline below a critical threshold, resulting in a variety of
symptoms such as pallor, sweating, shakiness, confusion and even
unconsciousness, coma and death. Hypoglycaemic symptoms can be very
Autonomic
vague and non-specific, so it is important to have a high level of suspicion
and to measure and document blood glucose levels in any child with any
of the symptoms listed in Table 1.

Causes of hypoglycaemia (Figure 1)

Endocrine
Hyperinsulinism: at times of hypoglycaemia, one of the body’s first
responses is to switch off insulin production. Therefore, the presence of
any measurable insulin when hypoglycaemia is proven is abnormal, even
Figure 1 Causes of hypoglycaemia beyond the neonatal period.
if the amount seems small.
The most common cause of hyperinsulinism is congenital
hyperinsulinism of infancy (CHI), also known as persistent potassium-sensitive ATP (KATP) channel in beta-cells, and loss of
hyperinsulinaemichypoglycaemiaofinfancy.Childrenwiththiscondition function of this channel is the most common identifiable cause of CHI.
often present during the neonatal period with severe, intractable Mutations in the ABCC8 and KCNJ11 genes on chromosome 11p15 have
hypoglycaemia, though some present later (typically in the first few been identified as the cause. This is the most severe form of CHI and is
months of life), usually at the time of an intercurrent illness when they often not amenable to treatment with medical therapies; in these cases,
are unable to meet their additional glucose requirements. The incidence pancreatectomy is the only effective therapeutic option. Inheritance of the
of CHI is about 1/30,000e50,000 live births, with wide geographical mutation can occur in an
variation; in some parts of the Arabian Peninsula, it occurs as commonly autosomalrecessivemanner,inwhichcasethereisusuallydiffuse
as 1/2500 live births. CHI is a heterogeneous condition with a variety of enlargement of the beta-cells throughout the pancreas. Sporadic
aetiologies that lead to the dysregulation casesareusuallyduetohomozygosityofapaternalmutationofthe
ofinsulinsecretionresultinginsevereandpersistenthypoglycaemia. Five ABCC8orKCNJ11geneswithspecificlossofthematernalallelesof the 11p15
different protein mutations have been found to cause CHI: the region, and result in a focal lesion.
sulfonylurea receptor 1 (SUR-1), Kir6.2, glucokinase, glutamate The five mutations listed above have very variable phenotypes; some
dehydrogenase (GDH) and the mitochondrial enzyme shortchain-3- children experience mild fasting hypoglycaemia that responds well to
hydroxyacyl-CoA dehydrogenase (SCHAD). Both SUR-1 and Kir6.2 are medication, while others have far more refractory problems. Islet cell
vital for the effective function of the morphology also varies; some have normal-sized islet cells and in others
they are enlarged. Other MODY mutations more commonly associated
with hyperglycaemia have also been implicated in transient
Possible features of hypoglycaemia hyperinsulinism, including hepatocyte nuclear factor 4-alpha.
Recently, hyperinsulinism in association with hypoglycaemia in a
disorder of fatty acid oxidation has been described in SCHAD
hyperinsulinism. The exact cause of the dysregulated insulin secretion
C
Irritability
has yet to be determined; these children also have increased levels of 3-
C
Lethargy, stupor, unconsciousness
hydroxybutyryl-carnitine in plasma and urinary 3hydroxyglutarate. It is
C
Poor feeding
inherited in an autosomal recessive manner, and affected children suffer
C
Hypotonia, floppiness C
fasting hypoglycaemia with varying degrees of severity. It usually
Hypothermia responds to treatment with diazoxide.
C
Cyanotic episodes, apnoea Hyperinsulinism as a cause of hypoglycaemia is also seen in
C
Tremor, seizures BeckwitheWeidemann syndrome (up to 50% of patients) and
C
Headache someformsofcongenitaldisordersofglycosylation(CDG-
C
Marked hunger Ia,CDGIbandCDG-Id).Thedegreeofhypoglycaemiavarieswidelyinboth
Table 1 of these groups of conditions and the precise pathophysiology of the
hyperinsulinism is not yet known. Both may respond to pharmacological
treatment, but some require pancreatectomy.
Once hyperinsulinism has been confirmed as the cause of
hypoglycaemia, treatment must be started to control blood glucose levels.

PAEDIATRICS AND CHILD HEALTH 23:4 153 2013 Published by Elsevier Ltd.
 SYMPOSIUM: DIABETES MELLITUS
A glucose requirement of more than 15 mg/kg/minute is highly
suggestive of hyperinsulinism and infusion of glucose at a rate of more
than 20 mg/kg/minute may be necessary. Once glucose levels are stable,
medical therapy can be started. The
firstlinepharmacologicaltreatmentiswithdiazoxideatupto15mg/kg/ day in
three divided doses, in combination with a thiazide diuretic
suchaschlorothiazide.Doseshigherthanthishavenotbeenshown to be
effective and are more likely to cause significant side effects
suchashypertensionandhypertrichosis(whichisalmostuniversal with
diazoxide treatment). If this regimen is not successful in maintaining
blood glucose levels above 3 mmol/litre, treatment with octreotide or
glucagon infusion may be necessary. Pancreatic surgery may also be
necessary, and so it is important to determine whether the
hyperinsulinism is due to diffuse or focal disease.
Previously, sampling of the pancreatic venous drainage during
hypoglycaemia was undertaken to try to differentiate between the two
disease entities and accurately locate any focal lesion before
pancreatectomy. Positron emission tomography is now used,
thoughthisiscurrentlyavailableonlyinhighlyspecializedcentres, the UK
centre being in Manchester. If a focal lesion is identified, surgical
removal can be curative. Diffuse disease is far more difficult to manage;
in some cases, 95% pancreatectomy is required, which can result in
enzyme deficiency and the subsequent development of insulin-dependent
diabetes.
In view of its rarity, management of CHI is a highly specialized area
and it is recommended that affected children are managed by teams with
appropriate expertise. There are currently two such centres in the UK,
one at Great Ormond Street Hospital, London and the other at the Royal
Manchester Children’s Hospital, Manchester.
Insulin resistance, as seen in type II diabetes, also causes
dysregulation of insulin secretion. However, before frank
hyperglycaemia develops, the high levels of insulin secreted in response
to food can be so extreme that postprandial hypoglycaemia can occur,
particularly with very high carbohydrate loads.
Occasionally, hyperinsulinism can be due to deliberate poisoning with
exogenous insulin. This can be differentiated from endogenous excess
insulin production by measuring Cpeptide at the time of the
hypoglycaemia and hyperinsulinism. If the C-peptide is low when insulin
is inappropriately raised, administration of exogenous insulin must be
strongly considered as a cause.
Adrenal insufficiency: adrenal failure can occur at any age and can be
due to a primary disease process affecting the adrenal glands directly, to
secondary suppression of the adrenal glands by drug administration, or to
pituitary failure. Cortisol is one of the important counter-regulatory
hormones secreted as glucose levels decline, and inadequate cortisol
levels lead to hypoglycaemia.
Addison’s disease is an autoimmune process in which adrenal
antibodies lead to destruction of the adrenal cortex, leading to
glucocorticoid and mineralocorticoid deficiency. Affected children may
present with hypoglycaemia, which is often unmasked by an intercurrent
illness, and are hyperpigmented due to stimulation of melanocytes by the
high levels of adrenocorticotropic hormone (ACTH) secreted by the
pituitary in an attempt to stimulate cortisol production in the failing
adrenal glands. They will often also have low sodium levels and raised
potassium levels, although hypo natraemia often appears in isolation
early on in the disease process.
Itmaybeassociatedwithotherautoimmunedisorderssuchastype1 diabetes,
autoimmune hypothyroidism, coeliac disease and autoimmune
polyendocrinopathyecandidiasiseectodermal dystrophy (APECED)
syndrome. The latter condition is inherited in an autosomal recessive
PAEDIATRICS AND CHILD HEALTH 23:4
manner and the diagnosis should be suspected in the presence of two of
three cardinal components: autoimmune adrenal failure, autoimmune
hypoparathyroidism and candidiasis. Diagnosis is confirmed by mutation
analysis of the AIRE gene.
Another inherited cause of adrenal failure is Allgrove’s or triple A
syndrome. Achalasia, alacrima and adrenal failure secondary to ACTH
resistance are the three main features, with autonomic dysfunction and
progressive neurological symptoms also often being problematic. It is
inherited in an autosomal dominant manner and is due to a mutation in
the ALADIN gene located on chromosome 12q.
In boys with proven adrenal failure, it is mandatory that
adrenoleukodystrophy is excluded as a cause. This is an X-linked
recessive disorder and is detected by high levels of very-long-chain fatty
acids in the urine. Adrenal failure may be the first symptom, with CNS
leukodystrophy leading to severe, progressive neurological deterioration.
There is also a much rarer and more severe infantile autosomal recessive
form. Adrenomyeloneuropathy is
anothervariationofthisdisorder,inwhichinsufficiencydevelopsin
childhood and adolescenceand neurological disease follows10e15
yearslater.Theonlytreatmentthathasbeenshowntobeeffectivein
preventing the progressive neurological deterioration is bone marrow
transplantation; Lorenzo’s oil has not been shown to alter the course of
the disease.
Other rare inherited causes of adrenal failure that present beyond the
neonatal period include familial glucocorticoid deficiency (due to
hereditary unresponsiveness to ACTH), Wolman disease and congenital
adrenal hypoplasia. The latter usually presents with adrenal failure in a
neonate, but sometimes do not become apparent until the child is several
months old.
Disruption of the hypothalamicepituitaryeadrenal (HPA) axis can also
cause adrenal failure. This can be due to tumours such as
craniopharyngioma, head injury or infection. Congenital hypopituitarism
may also not be diagnosed until a baby is several months old, with ACTH
deficiency causing relative adrenal insufficiency. In adults, biochemical
evidence of ACTH deficiency post-traumatic brain injury has been
demonstrated in as many as 60% of patients, though its clinical
significance is uncertain. There is little evidence of similar problems in
children; this may be because it is not a problem, or perhaps because it
has simply not been looked for. Prospective studies of endocrine
outcomes in children who have suffered head injury are ongoing.
Iatrogenic disruption of the HPA axis with corticosteroids is widely
recognized. High-dose inhaled corticosteroids (in particular fluticasone)
have been found to cause secondary adrenal failure, so taking a careful
drug history is important in any child in whom adrenal failure is
suspected. Cranial spinal irradiation can also lead to ACTH deficiency,
even many years later, and it is important that children who have received
such treatment are kept under regular intermittent follow-up, even into
adulthood.
Growth hormone (GH) deficiency: babies with GH deficiency may
present with recurrent, persistent hypoglycaemia; abnormal growth is
often not seen until after the first year of life. However growth hormone
deficiency in isolation is very rarely a cause of hypoglycaemia at this age;
multiple pituitary hormone deficiencies (MPHD) must be looked for and
excluded, especially ACTH deficiency. These children may have other
features of MPHD, such as abnormal eye movements or vision, persistent
jaundice or mid-line defects. Recurrent hypoglycaemia with documented
GH deficiency is a clear indication to start GH treatment, even if the baby
is growing well and normally, as it can be a cause of sudden death.
Hypoglycaemia is not always a very good stimulus for GH release, so
low a GH level in hypoglycaemia does not definitely indicate GH
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 SYMPOSIUM: DIABETES MELLITUS
deficiency. GH deficiency should be confirmed with an appropriate
stimulation test.
SilvereRussellsyndrome:childrenwithSilvereRussellsyndrome are small-
for-gestational-age at birth and continue to grow poorly throughout
childhood. As well as characteristic triangular faces,
theyhaveclinodactylyandoftenasymmetryoflimblength.Feeding is often
extremely difficult and some children require gastrostomy or nasogastric
feeding to ensure adequate calorific intake. Some
childrenalsohaveassociatedGHdeficiencybuteventhosewhoare GH
sufficient may have problems with recurrent hypoglycaemia, usually on
fasting. The diagnosis of SilvereRussell syndrome is made on clinical
grounds and should be considered in small-forgestational-age children
who fail to exhibit catch-up growth and who have problems with
hypoglycaemia and/or feeding.
Inborn errors of metabolism
Disorders of mitochondrial fatty acid oxidation: medium-chain acetyl-
CoA dehydrogenase deficiency (MCADD) is an autosomal recessive
disorder of fatty acid oxidation that affects the body’s ability to
breakdown fat during periods of fasting. This means that the production
of ketone bodies from FFAs is limited and so hypoglycaemia occurs after
a prolonged fast or with inadequate intake (e.g. during an intercurrent
illness). It is the commonest of the mitochondrial fatty acid beta-
oxidation defects and has an incidence of about 1/10,000 live births
(which is similar to that of phenylketonuria).
Affected children classically present with hypoglycaemia at the time
of an often mild intercurrent illness, between the age of 3 months and 3
years.Atothertimes,they are usually asymptomatic. The
hypoglycaemiacanbesevere,causingseizures,andcanleadto significant
long-term morbidity. In the 1990s, 22% of children presenting with
MCADdeficiency died, and it canbea causeof sudden unexpected death
in infancy. Due to the defect in fatty acid metabolism, ketosis does not
occur and thus the hypoglycaemia is hypoketotic. Plasma
octanoylcarnitine levels are elevated and urinary amino acid excretion is
abnormal; detection of octanoylcarnitine, phenylpropionylglycine and
hexanoylglycine in the urine is
diagnostic.Oncethedisorderhasbeenidentified,itispossibletoprevent
hypoglycaemia by avoiding prolonged periods of fasting, using glucose
polymer drinks during illnesses, and ensuring prompt treatment with
intravenous glucose solutions if oral intake is
inadequate.Episodesofhypoglycaemiatendtobecomelessproblematic as
children get older and fasting tolerance improves.
MCADD has been included in newborn screening programmes
elsewhere in the world (including Australia and Germany) for over a
decade, and is done by measuring octanoylcarnitine in blood spots. Since
Feb 2009, all newborn babies in the UK are routinely screened for
MCADD as part of the standard newborn screening blood test performed
on day 5 of life.
Other defects of mitochondrial fatty acid oxidation that cause
hypoglycaemia include long-chain-very-long-chain acyl-CoA
dehydrogenase deficiency and long-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency. Affected children have episodes of
hypoketotic hypoglycaemia, but often have other manifestations
including muscle weakness, cardiomyopathy and liver disease.
Treatment involves avoiding prolonged fasting (more than 10e 12 hours);
some children have required continuous feeding to maintain
normoglycaemia. The diagnosis can be made by urinary organic and
amino acid analysis during the hypoglycaemic episode, as affected
children may produce no abnormal metabolites when they are clinically
well.
PAEDIATRICS AND CHILD HEALTH 23:4
Disorders of carnitine metabolism: primary carnitine deficiency is
another cause of hypoketotic hypoglycaemia and is inherited in an
autosomal recessive manner. Affected individuals also present with
cardiomyopathy and/or skeletal myopathy. Reduced plasma carnitine
levels, particularly at times of hypoglycaemia, should raise suspicion of
the disease, which can be confirmed by measuring carnitine transport in
the patient’s fibroblasts; this is markedly reduced, usually to less than 5%
of normal. Carnitine levels are often also low in MCADD.
Carnitine is transported into the mitochondria by carnitine
palmitoyltransferase (CPT) 1 and 2. CPT1 deficiency leads to
hypoketotic hypoglycaemia, hepatomegaly and deranged liver function
(raised transaminases), renal tubular acidosis and myopathy
characterized by elevated creatinine kinase levels. There is also an
infantile form that presents with seizures, coma and cardiomyopathy
shortly after birth. Elevated urinary dicarboxylic acids of chain length
C6eC10 confirm the diagnosis.
CPT2 deficiency has two phenotypes. The ‘benign’ form presents in
adulthood with rhabdomyolysis after prolonged exercise; the ‘severe’
infantile form presents with hypoketotic hypoglycaemia and sometimes
major cardiac involvement leading to sudden death before the age of 1
year. Treatment comprises avoidance of prolonged fasting, a low-fat diet
enriched with medium-chain triglycerides, and carnitine
supplementation.
Glycogen storage disorders: glucose is stored as glycogen primarily in
the liver but also in muscle and the kidneys. If there are defects in the
formation of glycogen or its breakdown to allow release of glucose,
hypoglycaemia can occur. Of the group of conditions known as glycogen
storage diseases (GSDs), GSD type I (von Gierke’s disease) is the
commonest one causing hypoglycaemia. Deficiency of glucose-6-
phosphatase means that glucose-6-phosphate cannot be broken down to
release glucose, with the result that glycogen stores accumulate
massively in the liver leading to marked hepatomegaly. As well as
recurrent hypoglycaemia, children with GSD type I have lactic acidosis,
elevated lipid levels and hyperuricaemia. Although classed as a GSD,
GSD type I is primarily a defect of gluconeogenesis. Treatment involves
prevention of hypoglycaemia by continuous nasogastric or gastrostomy
feeding and cornflour. Diagnosis is made by enzymatic studies of liver,
kidney or intestinal biopsy tissue or by looking for specific gene
mutations.
ThetwootherGSDsassociatedwithhypoglycaemiaareGSDtype
III,duetoamylo-1,6-glucosidasedeficiency,andGSDtypeVI,which is
caused by liver phosphorylase deficiency. Type III patients have
biochemicalproblemssimilartothosewithtypeI,plusshortstature and
sometimes cardiomyopathy and myopathy. GSD type VI has a
comparatively benign course, with mild episodes of hypoglycaemia not
usually associated with lactic acidaemia or hyperuricaemia. Affected
children still have hepatomegaly and also growth retardation, and may
have problems with hypotonia and muscle weakness, raised
transaminases and hyperlipidaemia. Most of these clinical features
resolve by puberty, though some
individualshaveproblemswithmyopathy,cardiomyopathy(whichmaybe
fatal) and renal tubular acidosis. The diagnosis is made by biochemical
studies of leucocytes.
Glycogen synthase deficiency (GSD type 0) is a rare but probably
under-diagnosed cause of hypoglycaemia. Hypoglycaemia on fasting is
ketotic and, unlike in the other GSDs, hepatomegaly is unusual.
Defects in amino acid metabolism: most amino or organic acidaemias
that feature hypoglycaemia as symptoms present during the neonatal
period (e.g. propionic acidaemia, maple syrup urine disease, 3-hydroxy-
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 SYMPOSIUM: DIABETES MELLITUS
3-methylglutaric aciduria). However, some children have a milder
phenotype, with symptoms not becoming apparent until they are several
months old. Unlike defects in fatty acid oxidation, these conditions
present with hyperketotic hypoglycaemia, with other clinical
manifestations such as developmental delay, hypotonia and metabolic
acidosis. It is important that these conditions are excluded before a
diagnosis of the essentially benign condition ketotic hypoglycaemia (see
below) is made in children who present with low blood glucose levels
and good ketone production.
Hereditary fructose intolerance: children with fructose intolerance have
no problems with hypoglycaemia until foods containing fructose are
introduced, often at weaning. This autosomal recessively inherited
condition is due to a deficiency of fructose1,6-bisphosphate aldolase and
affected individuals suffer hypoglycaemia and severe abdominal pain
when fructose or cognate sugars are eaten. Avoidance of such sugars
often becomes automatic in affected children, whereas persistent
ingestion leads to liver and kidney injury plus poor growth.
Galactosaemia: deficiency of galactose-1-phosphate uridyltransferase
prevents galactose metabolism, and the toxic accumulation of galactose-
1-phosphate leads to hepatic impairment, hepatomegaly, hypoglycaemia
with ketones and predisposition to sepsis, particularly caused
byEscherichiacoli. Hypoglycaemia is usuallyonly seen once liver
impairment has developed, and any infant who presents with
hypoglycaemia, jaundice and gastrointestinal upset should be
screenedforgalactosaemia.Treatmentisbyeliminationofgalactose from the
diet, which reverses most of the changes and should prevent long-term
neurological and hepatic damage.
Others: there are numerous other, very rare inborn errors of metabolism
that canpresent with hypoglycaemia, which is usually hypoketotic.
Recently described syndromes include dopamine bhydroxylase
deficiency, which is characterized by autonomic dysfunction (mainly
profound hypotension, particularly on standing) and hypoglycaemia.
Some respiratory chain defects can
alsopresentwithhypoglycaemiaaloneandsoshouldbeconsidered in the
differential diagnosis of metabolic causes of hypoglycaemia. Not all of
these disorders can be detected when the affected person is well, as
abnormal metabolites may be present only at the time of
acutedecompensation.Forthisreason,itisimportanttoensurethat
aurinesampleiscollectedatthetimeofhypoglycaemiaandsentfor analysis of
organic and amino acids.
Poisoning
Many drugs can cause hypoglycaemia as a side effect, directly or
indirectly (e.g. adrenal suppression with inhaled corticosteroids). A
careful drug history of both the child and other family members is
important in any child presenting with hypoglycaemia. Common causes
of hypoglycaemia due to poisoning are sulfonylurea ingestion,
paracetamol overdose and administration of insulin. Treatment is with
glucose plus the appropriate antidote when relevant (e.g. N-
acetylcysteine in paracetamol poisoning). If glucose alone is insufficient
in maintaining normoglycaemia with hyperinsulinism secondary to
poisoning, there are reports of successful use of diazoxide or octreotide
as an adjunct.
Ingestion of plants such as cocklebur (Xanthium strumarium) can
cause hypoglycaemia along with renal and liver toxicity, and in large
amounts can cause multi-organ failure and death.
Treatment is supportive.
PAEDIATRICS AND CHILD HEALTH 23:4
Sepsis
Severe infections can lead to hypoglycaemia, partly due to increased use
of glucose and partly due to inadequate gluconeogenesis as a result of the
sepsis. Worldwide, malaria is a wellrecognized cause of hypoglycaemia
and must be treated aggressively to avoid severe morbidity or even death.
In developing nations where children’s nutritional status may be
suboptimal, any serious infection can lead to hypoglycaemia and
significantly affect the outcome.
Ketotic hypoglycaemia
Idiopathic ketotic hypoglycaemia is the commonest cause of
hypoglycaemia in children and is a diagnosis of exclusion. As techniques
for identifying errors of metabolism become ever more sophisticated, it
may eventually become an obsolete diagnosis. Recent research has
demonstrated that children who have ketotic hypoglycaemia have lower
levels of gluconeogenic substrate and glucose production than normal
controls. It is not known whether this represents an extreme variation of
normal or is due to as yet undiscovered defects in the gluconeogenesis
pathway.
Children withketotic hypoglycaemia typicallypresent between
theageof18monthsand7years,oftenafteraprolongedfastinthe context of an
intercurrent illness such as gastroenteritis.
Hypoglycaemia can be avoided by ensuring regular food intake and
ensuring that prolonged (more than 12 hours) periods of fasting are
avoided. It resolves spontaneously with time and is rarely seen after
puberty. Some children suffer hypoglycaemia to a sufficient degree to
trigger a seizure; however, neurological sequelae are very rare and
development is usually normal with no evidence of other organ
dysfunction.
Recognition and management of hypoglycaemia
Recognition of hypoglycaemia is important for appropriate treatment and
investigations. The symptoms of hypoglycaemia can be varied and non-
specific (Table 1). Measurement of glucose using standard bedside
testing monitors alone is not recommended, as
Investigation of hypoglycaemia
Plasma Urine
Confirm hypoglycaemia with laboratory Organic and amino acids
glucose level
Liver function tests Microscopy, culture and
sensitivity if sepsis is a
possibility
Insulin (C-peptide if exogenous insulin is
a possible cause)
Cortisol
Growth hormone
Free fatty acids and
b-hydroxybutyrate
Blood gas
Lactate and ammonia
Organic acids
Amino acids
Store and save additional sample if
possible for further investigations
(e.g. acylcarnitine)
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 SYMPOSIUM: DIABETES MELLITUS

Samples should be taken before treatment when possible. Arnoux J-B, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism:
currenttrendsindiagnosisandtherapy.OrphanetJRareDis2011;6:63.
Table 2 Hussain K, Dunne MJ. Hypoglycaemia. In: Brook CGD, Clayton PE, Brown RS,
eds. Brook’s clinical pediatric endocrinology. 5th Edn.
they are notoriously imprecise at low blood glucose levels. It is Oxford: Blackwell, 2005; 474e91.
importantthataformallaboratoryglucosetestisundertakenatthe same time Hyperinsulinism on www.diabetesgenes.org.
to confirm the true blood glucose level. This should be sent in a fluoride- Mochel F, Slama A, Touati G, et al. Respiratory chain defects may present
containing tube to prevent glycolysis and only with hypoglycemia. J Clin Endocrinol Metab 2005; 90: 3780e5.
spuriouslylowbloodglucoselevels.Nearpatienttestingofbloodketone
Senard JM, Rouet P. Dopamine beta-hydroxylase deficiency. Orphanet J Rare
levels can be helpful to exclude excess insulin as a cause.
Dis 2006; 30: 1e7.
Determination of the cause of hypoglycaemia is as important as
Weinstein DA, Correia CE, Saunders AC, et al. Hepatic glycogen synthase
appropriate treatment, to prevent its recurrence. While it is vital to raise
deficiency: an infrequently recognized cause of ketotic hypoglycemia.
blood glucose to a safe level as quickly as possible, blood samples to
investigate the cause of the hypoglycaemia should be taken before Mol Genet Metab 2006; 87: 284e8.
treatment is given, if possible (Table 2). The first urine passed after www.newbornbloodspot.screening.nhs.uk.
treatment for the hypoglycaemic episode should also be collected and
sent for analysis (Table 2); this can be a bag urine sample in small
children.
Practice points
Emergency treatment of symptomatic hypoglycaemia is by
promptadministrationof10%glucosesolutionatadoseof2e5ml/ kg i.v. Use C
Hypoglycaemia is defined as a plasma glucose level less than 2.8
of more than 10% dextrose solutions initially is not recommended mmol/litre
because of reports of severe hyperglycaemia due to inappropriateover- C
Blood samples to investigate the cause should be taken before
treatment.Glucoselevelsshouldberechecked15 minutes after the bolus to
ensurethatthey have normalized and the bolus should repeated if they treatment is given and the first urine passed after treatment
have not. The goal of treatment is to maintain the child’s blood glucose should be sent for metabolic screening
level at over 3.2 mmol/litre. It may be necessary to start an infusion of C
Prompt treatment of symptomatic hypoglycaemia, with IV therapy
10% glucose solution at a rate of 5 ml/kg/hour (which provides if necessary, is vital to prevent severe neurological sequelae
approximately 8 mg/kg/ minute of glucose) and a glucose requirement C
Absent ketone response and ongoing intravenous glucose
greater than this can be a clue to the underlying diagnosis (see CHI requirements of more than 15 mg/kg min1 are highly suggestive
above). If the child is conscious and otherwise well, intravenous therapy
of hyperinsulinism
can be discontinuedonceheorsheiseatinganddrinkingnormally,butglucose C
Recurrent hypoglycaemia should be formally investigated to exclude
levelsmustbemonitoredcarefullytoensurethattheyaremaintained in the
normal range (3.8e6.7 mmol/litre for non-fasting samples). a serious underlying cause
Children who have had proven, symptomatic hypoglycaemia (plasma
C
Ketotic hypoglycaemia is a diagnosis of exclusion once all sinister
glucose on a lab sample of less than 2.8 mmol/litre) should be admitted causes of hypoglycaemia have been discounted
to hospital and observed closely with monitoring of blood glucose,
initially hourly.
Long-term management and prevention of recurrence of
hypoglycaemia depends on finding the underlying cause (see above for
the treatment of specific disorders). The parents should
begivenabloodglucosemonitorandtaughthowtomeasureblood glucose
levels at home. In those who have recurrent episodes of hypoglycaemia,
it is important to ensure that the child can maintain normoglycaemia for
a safe period of fasting. This is usually considered to be the length of time
that a child of that age would normally sleep, so babies need to be able to
last 4e6 hours, while older children should be expected to last 12e16
hours.
Many children present to hospital with an isolated episode of
hypoglycaemia in the context of a prolonged fast associated with
intercurrent gastroenteritis and no specific cause can be found.
With these children, advice about regular intake of fluids containing
glucose during periods of illness is usually sufficient to prevent a
recurrence. The mainstay of the long-term management of the various
causes of hypoglycaemia is to avoid its recurrence wherever possible and
thus reduce the longterm risks of significant neurological morbidity and
mortality.A

FURTHER READING
Advanced paediatric life support. 5th Edn 2011.

PAEDIATRICS AND CHILD HEALTH 23:4 157 2013 Published by Elsevier Ltd.