HYPOGLYCAEMIA

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HYPOGLYCAEMIA IN INFANCY AND CHILDHOOD Practical
advice
J V Leonard UCL Institute of Child Health, London
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IMPORTANCE OF HYPOGLYCAEMIA
1. Acute illness 2. Long term complications
mental retardation 3. Genetic implications
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HYPOGLYCAEMIA
STANDARD DEFINITION
Blood glucose lt 2 (or 2.2) mmol/l
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HYPOGLYCAEMIA
HOW TO DEFINE
1. Symptoms
2. Outcome
3. Neurological changes
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HYPOGLYCAEMIC SYMPTOMS
Neuroglycopenia Fits Lethargy Confusion Visual
disturbances Behaviour disturbance Dysarthria/
ataxia Parasthesiae Headache Focal neurological
signs Coma
Catecholamine induced Anxiety Sweating Palpitatio
ns Pallor Tremulousness Weakness Hunger Abdominal
pain Nausea/vomiting
But may be asymptomatic in healthy children See
Chaussain JL. Glycemic response to 24 hour fast
in normal children and children with ketotic
hypoglycemia. J Pediatr. 1973 Mar82(3)438-43
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HYPOGLYCAEMIA
OUTCOME
Study 661 Premature newborns
Definition Blood glucose lt 2.6 mmol/l
Results

• 433 infants met definition of the study

• Recurrent hypoglycaemia on gt 3 days in 104
  infants

• Number of days on which hypoglycaemia recorded
• strongly correlated with mental and
• motor outcome at 18 months

Lucas A, Morley R, Cole TJ. Adverse
neurodevelopmental outcome of moderate neonatal
hypoglycaemia. BMJ. 1988 Nov 19297(6659)1304-8
.
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GLYCOGEN STORAGE DISEASE TYPE 1
GLYCOGEN
Glucose-1-P
Endoplasmic reticulum
Glucose
Glucose-6-P
Glucose-6-P
Phosphatase GSD1a
Glycolysis
Translocase GSD 1b
Pyruvate
Lactate
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GLYCOGEN STORAGE DISEASE TYPE 1
After a short fast marked hypoglycaemia hypok
etosis lactic acidosis
Untreated may remain asymptomatic with very
low blood glucose concentrations and high
lactate
Treated At risk of severe hypoglycaemia
lactate suppressed
Lesson Importance of alternative fuels
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HYPERINSULINAEMIC HYPOGLYCAEMIA IN INFANCY
Inappropriately raise insulin concentrations
whilst hypoglycaemic

• Increased glucose utilisation rate
  (particularly neonates)

• Detectable insulin with blood glucose lt 3 mmol/l

• Lipolysis and ketogenesis suppressed

• Branched chain aminoacid concentrations low

no alternative fuel
OUTCOME Always guarded - often poor
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HYPOGLYCAEMIA
Factors affecting outcome
1. Glucose concentration
2. Duration and frequency of hypoglycaemia
3. Diagnosis presence of an alternative fuel
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HYPOGLYCAEMIA
HOW TO DEFINE
1. Symptoms
2. Outcome
3. Neurological changes
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NEUROLOGICAL CHANGES DURING HYPOGLYCAEMIA
Brain stem auditory evoked potentials and
Somatosensory evoked potentials both changed
at blood glucose concentrations lt2.6 mmol/l
These changes are reversible in the short term
Koh TH, Aynsley-Green A, Tarbit M, Eyre JA.
Neural dysfunction during hypoglycaemia. Arch
Dis Child. 1988 Nov63(11)1353-8.
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HYPOGLYCAEMIA
Current definition lt 2.6 mmol/l
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HYPOGLYCAEMIA
Clinical diagnosis

• Any very sick child

• Undiagnosed seizures even if labelled as a
  febrile convulsion

• Any unexplained recurrent symptoms

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HYPOGLYCAEMIA
If suspected, must measure blood glucose

• Bedside stix are convenient - but are
  they satisfactory?
• In many studies poor precision and accuracy at
  critical blood glucose concentrations

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HYPOGLYCAEMIA

• Bedside stix are only a screening test

• If strip glucose is low, measure glucose in
  laboratory
• and hypoglycaemia screen
• or at least store some plasma frozen

MUST HAVE QUICK ANSWER!
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HYPOGLYCAEMIA
TREATMENT

• If co-operative give drink orally
• If not co-operative give glucose 200mg/kg
• intravenously

Monitor response of blood glucose
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HYPOGLYCAEMIA
Need to identify cause
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HYPOGLYCAEMIA
Aetiology 1. Endocrine 2. Metabolic 3.
Hepatic 4. Others
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HYPOGLYCAEMIA
Aetiology Endocrine Hyperinsulinaemia Adrenal
disease Growth hormone deficiency Hypopituitaris
m (Glucagon deficiency) (Catecholamine
deficiency)
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HYPERINSULINAEMIA IN INFANCY
AETIOLOGY
Single gene disorders ABCC8,KCNJ11, GLUD1,
GCK, HADH, HNF4A, SLC16A1
Syndromic Beckwith-Wiedemann, Soto, Kabuki,
Usher, Timothy, Costello, Trisomy 13, Mosaic
Turner
Metabolic disorders Tyrosinaemia type 1, CDG
type 1 a/b/d
Transient Perinatal asphyxia, Rhesus disease,
IUGR
Others
Requires urgent specialist management
Kapoor RR, Flanagan SE, James C, Shield J, Ellard
S, Hussain K. Hyperinsulinaemic hypoglycaemia.
Arch Dis Child. 2009 Jun94(6)450-7.
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HYPOGLYCAEMIA
Aetiology Metabolic Glycogen storage
disease Defects of gluconeogenesis Disorders of
?-oxidation and ketogenesis Respiratory chain
disorders (involving the liver) Organic
acidaemias Tyrosinaemia type 1 (Ketotic
hypoglycaemia)
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HYPOGLYCAEMIA
Aetiology Hepatic Acute liver failure of any
cause Cirrhosis of any cause
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HYPOGLYCAEMIA
Aetiology Others Severe illness shock sepsis
severe malnutrition Poisoning
alcohol insulin sulphonylureas,
etc b-blockers Malaria
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INVESTIGATIONS FOR HYPOGLYCAEMIA during
hypoglycaemia
1. Endocrine B UE, insulin (C-peptide) ,
cortisol (GH, glucagon) 2. Metabolic B glucose,
lactate (pyruvate), (ammonia) 3-hydroxybutyrate
(acetoacetate) free fatty acids, acyl
carnitines, free and total carnitine U keto
nes, organic acids 3. Hepatic B LFTs,
clotting 4. Others B/U Toxicology, ethyl
alcohol, etc
B blood or plasma U urine
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ESSENTIAL INVESTIGATIONS FOR HYPOGLYCAEMIA during
hypoglycaemia (minimum set)
1. Endocrine B UE, insulin , cortisol 2.
Metabolic B glucose, lactate 3-hydroxybutyrate
free fatty acids, acyl carnitines, U
ketones, organic acids 3. Hepatic B LFTs,
clotting 4. Others B/U Toxicology ( if indicated)
B blood or plasma U urine
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INVESTIGATION OF HYPOGLYCAEMIA
Supervised fasts if no samples or hypoglycaemia
suspected for 1. Diagnosis 2.
Management
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RESPONSE TO HYPOGLYCAEMIA
Insulin undetectable lt 2 - 5 mU/l
lt 25 pmol/l Cortisol gt400 nmol/l Growth
hormone gt15 mU/l
Free fatty acid /ketone ratio use graph
Morris AA, Thekekara A, Wilks Z, Clayton PT,
Leonard JV, Aynsley-Green A. Evaluation of fasts
for investigating hypoglycaemia or suspected
metabolic disease. Arch Dis Child. 1996
Aug75(2)115-9.
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DIAGNOSTIC FASTS
1. Measure blood spot acyl carnitines before
fast.
2. The fast must be properly supervised
3. The full range of investigations must be
completed
4.The fast must continue long enough
Please do not attempt this if these conditions
cannot be met.
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SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED
METABOLIC DISEASE
Morris AA, Thekekara A, Wilks Z, Clayton PT,
Leonard JV, Aynsley-Green A. Evaluation of fasts
for investigating hypoglycaemia or suspected
metabolic disease. Arch Dis Child. 1996
Aug75(2)115-9.
Total fasts 138 Final blood glucose lt2.6
mmol/l 54 ( 39) lt1.5 mmol/l
4 ( 3) unwell 1 (
lt1) Diagnoses 30 ( 22) Inadequate
fast 16 ( 12)
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SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED
METABOLIC DISEASE
Morris AA, Thekekara A, Wilks Z, Clayton PT,
Leonard JV, Aynsley-Green A. Evaluation of fasts
for investigating hypoglycaemia or suspected
metabolic disease. Arch Dis Child. 1996
Aug75(2)115-9.
Diagnoses Hyperinsulinaemia 12 Defects of
?-oxidation /ketogenesis 7 Others 11
Total 30 Ketotic hypoglycaemia 32
Note the value of a negative result
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SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED
METABOLIC DISEASE
Diagnostic yield if Documented
hypoglycaemia 22/79 (28) Only suspected
hypoglycaemia 1/30 ( 3)
Morris AA, Thekekara A, Wilks Z, Clayton PT,
Leonard JV, Aynsley-Green A. Evaluation of fasts
for investigating hypoglycaemia or suspected
metabolic disease. Arch Dis Child. 1996
Aug75(2)115-9.
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Diagnostic path for recurrent hypoglycaemia in
children
To be tested
Specimens from hypoglycaemic episode
yes
no
? diagnosis
History exam
no
yes
explicable no need to investigate
? diagnostic clues
Possible diagnosis
Further investigations as appropriate synacthen
test, pituitary function tests, Urine organic
acids, DNA Mutation analysis, etc.
Unexplained with no clues
Next page
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Further investigations as appropriate synacthen
test, pituitary function tests, Urine organic
acids, DNA Mutation analysis, etc.
Unexplained with no clues
yes
Abnormal acyl carnitines
Blood spot acyl carnitines
? Diagnosis
normal
no
Diagnostic fast
Next page
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Diagnostic fast
no
? hypoglycaemia BS lt 2.6 mmol/l
If FFA gt 1 mmol/l may still be useful diagnostic
information
yes
yes
no
? Detectable insulin Plasma insulin gt5 mU/l
? C-peptide detectable
Exogenous insulin
yes
no
Hyperinsulinaemia note FFA,ketones low and in
neonates cortisol also
Next page
36
yes
Adrenal disease Hypopituitarism
? Cortisol lt200 nmol/l
ACTH, etc
no
Check height velocity ? low
yes
? Growth hormone lt 15 mU/l
no
yes
no
Glucagon test
? Raised blood lactate during fast gt 2.5 mmol/l
- either persistent raised or steadily
increasing during fast
GSD 1 Fructose 1,6 bisphosphatase def. Long chain
fat oxidation disorders Respiratory chain
disorders All may be hypoketotic
yes
no
Next page
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? FFA/ketone ratio use graph
Disorder of fatty acid oxidation
increased
Ketone body utilisation defect
decreased
normal
Glycogen storage disease type III and disorders
of phosphorylase cascade
?hepatomegaly
yes
no
Ketotic hypoglycaemia Adrenal disorders - see
above Growth hormone deficiency in infants
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? FFA/ketone ratio use graph
Disorder of fatty acid oxidation
increased
Ketone body utilisation defect
decreased
normal
Glycogen storage disease type III and disorders
of phosphorylase cascade
?hepatomegaly
yes
no
Ketotic hypoglycaemia Adrenal disorders - see
above Growth hormone deficiency in infants
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HYPOGLYCAEMIA
Ketotic hypoglycaemia

• - Usually preschool child
• - Often unwell and misses evening meal
• - Found unwell next morning floppy or fitting
• - rapid recovery with glucose
• improves with age
• - outcome almost uniformly good

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KETOTIC HYPOGLYCAEMIA
Recent experimental studies
Bodamer OA, Hussein K, et al Glucose and leucine
kinetics in idiopathic ketotic hypoglycaemia.
Arch Dis Child. 2006 Jun91(6)483-6. ,
Huidekoper HH, Duran M, et al Fasting adaptation
in idiopathic ketotic hypoglycemia a mismatch
between glucose production and demand. Eur J
Pediatr. 2008 Aug167(8)859-65.
? glucose production rates
? glycogenolysis and gluconeogenesis
? leucine oxidation rates
? plasma alanine concentrations
? plasma ketones
?Ketone utilisation ?
? Reduced / immature fasting tolerance
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HYPOGLYCAEMIA IN CHILDREN
CONCLUSIONS
1. Hypoglycaemia is an important problem 2.
Diagnosis most easily made if correct
specimens are collected when hypoglycaemic
AND
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GLUCOSE TRANSPORTER DEFICIENCY (GLUT1 deficiency)

• Early onset epileptic encephalopathy
• unusual fits only occasionally worse with
  fasting
• resistant to anticonvulsants
• Developmental delay
• Complex movement disorder - speech , ataxia,
  etc

Diagnosis CSF /blood glucose lt 0.4 - 0.46 CSF
lactate low mutations in GLUT1 (
heterozygous) RBC glucose uptake studies