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HYPOGLYCAEMIA
IN INFANCY AND CHILDHOOD
Practical advice
J V Leonard
UCL Institute of Child Health, London
IMPORTANCE OF HYPOGLYCAEMIA
1. Acute illness
2. Long term complications – mental retardation
3. Genetic implications
HYPOGLYCAEMIA
‘STANDARD’ DEFINITION
Blood glucose
< 2 (or 2.2) mmol/l
HYPOGLYCAEMIA
HOW TO DEFINE
1. Symptoms
2. Outcome
3. Neurological changes
HYPOGLYCAEMIC SYMPTOMS
Catecholamine induced
Neuroglycopenia
Anxiety
Sweating
Palpitations
Pallor
Tremulousness
Weakness
Hunger
Abdominal pain
Nausea/vomiting
Fits
Lethargy
Confusion
Visual disturbances
Behaviour disturbance
Dysarthria/ ataxia
Parasthesiae
Headache
Focal neurological signs
Coma
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 Mar;82(3):438-43
HYPOGLYCAEMIA
OUTCOME
Study: 661 Premature newborns
Definition: Blood glucose < 2.6 mmol/l
Results:
• 433 infants met definition of the study
• Recurrent hypoglycaemia on > 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 19;297(6659):1304-8.
GLYCOGEN STORAGE DISEASE TYPE 1
GLYCOGEN
Glucose-1-P
Glucose-6-P
Glycolysis
Glucose-6-P
Translocase
GSD 1b
Pyruvate
Lactate
Endoplasmic
reticulum
Glucose
Phosphatase
GSD1a
GLYCOGEN STORAGE DISEASE TYPE 1
After a short fast
marked hypoglycaemia
hypoketosis
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
HYPERINSULINAEMIC HYPOGLYCAEMIA IN INFANCY
Inappropriately raise insulin concentrations whilst hypoglycaemic
• Increased glucose utilisation rate (particularly neonates)
• Detectable insulin with blood glucose < 3 mmol/l
• Lipolysis and ketogenesis suppressed
• Branched chain aminoacid concentrations low
= no alternative fuel
OUTCOME Always guarded - often poor
HYPOGLYCAEMIA
Factors affecting outcome
1. Glucose concentration
2. Duration and frequency of hypoglycaemia
3. Diagnosis – presence of an alternative fuel
HYPOGLYCAEMIA
HOW TO DEFINE
1. Symptoms
2. Outcome
3. Neurological changes
NEUROLOGICAL CHANGES DURING HYPOGLYCAEMIA
Brain stem auditory evoked potentials
and
Somatosensory evoked potentials
both changed at blood glucose concentrations <2.6 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 Nov;63(11):1353-8.
HYPOGLYCAEMIA
Current definition
< 2.6 mmol/l
HYPOGLYCAEMIA
Clinical diagnosis
• Any very sick child
• Undiagnosed seizures even if labelled as a ‘febrile convulsion’
• Any unexplained recurrent symptoms
HYPOGLYCAEMIA
If suspected, must measure blood glucose
Q. Bedside ‘stix’ are convenient
-
but are they satisfactory?
In many studies poor precision and accuracy at critical blood
glucose concentrations
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!
HYPOGLYCAEMIA
TREATMENT
• If co-operative
give drink orally
• If not co-operative give glucose 200mg/kg
intravenously
Monitor response of blood glucose
HYPOGLYCAEMIA
Need to identify cause
HYPOGLYCAEMIA
Aetiology
1. Endocrine
2. Metabolic
3. Hepatic
4. Others
HYPOGLYCAEMIA
Aetiology
Endocrine
Hyperinsulinaemia
Adrenal disease
Growth hormone deficiency
Hypopituitarism
(Glucagon deficiency)
(Catecholamine deficiency)
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 Jun;94(6):450-7.
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)
HYPOGLYCAEMIA
Aetiology
Hepatic
Acute liver failure of any cause
Cirrhosis of any cause
HYPOGLYCAEMIA
Aetiology
Others
Severe illness shock
sepsis
severe malnutrition
Poisoning
Malaria
alcohol
insulin
sulphonylureas, etc
-blockers
INVESTIGATIONS FOR HYPOGLYCAEMIA
during hypoglycaemia
1. Endocrine B
U&E, 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
ketones, organic acids
3. Hepatic
B
LFTs, clotting
4. Others
B/U
Toxicology, ethyl alcohol, etc
B = blood or plasma U = urine
ESSENTIAL INVESTIGATIONS FOR HYPOGLYCAEMIA
during hypoglycaemia (minimum set)
1. Endocrine B
U&E, 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
INVESTIGATION OF HYPOGLYCAEMIA
Supervised fasts if no samples or hypoglycaemia suspected
for
1. Diagnosis
2. Management
RESPONSE TO HYPOGLYCAEMIA
Insulin
undetectable < 2 - 5 mU/l
< 25 pmol/l
Cortisol
>400 nmol/l
Growth hormone
>15 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 Aug;75(2):115-9.
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.
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 Aug;75(2):115-9.
Total fasts
138
Final blood glucose
<2.6 mmol/l
54 ( 39%)
<1.5 mmol/l
4 ( 3%)
unwell
1 ( <1%)
Diagnoses
30 ( 22%)
Inadequate fast
16 ( 12%)
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 Aug;75(2):115-9.
Diagnoses
Hyperinsulinaemia
Defects of -oxidation /ketogenesis
Others
Total
Ketotic hypoglycaemia
Note the value of a negative result
12
7
11
30
32
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 Aug;75(2):115-9.
Diagnostic path for recurrent hypoglycaemia in children
To be tested
Specimens from hypoglycaemic episode
no
yes
? 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
? FFA/ketone ratio
use graph
increased
Disorder of fatty acid oxidation
decreased
Ketone body utilisation defect
normal
?hepatomegaly
yes
Glycogen storage disease
type III and
disorders of phosphorylase cascade
no
“Ketotic hypoglycaemia”
Adrenal disorders - see above
Growth hormone deficiency in infants
HYPOGLYCAEMIA
Ketotic hypoglycaemia
- Usually preschool child
- Often unwell and misses evening meal
- Found unwell next morning :
- rapid recovery with glucose
- improves with age
- outcome almost uniformly good
floppy or fitting
KETOTIC HYPOGLYCAEMIA
Recent experimental studies
Bodamer OA, Hussein K, et al Glucose and leucine kinetics in idiopathic ketotic hypoglycaemia. Arch Dis Child.
2006 Jun;91(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 Aug;167(8):859-65.
 glucose production rates
 glycogenolysis and gluconeogenesis
 leucine oxidation rates
 plasma alanine concentrations
 plasma ketones
Ketone utilisation ?
? Reduced / immature fasting tolerance
HYPOGLYCAEMIA IN CHILDREN
CONCLUSIONS
1. Hypoglycaemia is an important problem
2. Diagnosis most easily made if correct
specimens are collected when hypoglycaemic
AND
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 < 0.4 - 0.46
CSF lactate low
mutations in GLUT1 ( heterozygous)
RBC glucose uptake studies