HYPOGLYCAEMIA IN INFANCY AND CHILDHOOD Practical advice J V Leonard UCL Institute of Child Health,...
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Transcript of HYPOGLYCAEMIA IN INFANCY AND CHILDHOOD Practical advice J V Leonard UCL Institute of Child Health,...
HYPOGLYCAEMIA
IN INFANCY AND CHILDHOOD
Practical advice
J V Leonard
UCL Institute of Child Health, London
1. Acute illness
2. Long term complications – mental retardation
3. Genetic implications
IMPORTANCE OF HYPOGLYCAEMIA
HYPOGLYCAEMIC SYMPTOMS
Catecholamine induced
AnxietySweatingPalpitationsPallorTremulousnessWeaknessHungerAbdominal painNausea/vomiting
Neuroglycopenia
Fits LethargyConfusionVisual disturbancesBehaviour disturbanceDysarthria/ ataxiaParasthesiae HeadacheFocal neurological signsComa
But may be asymptomatic in healthy childrenSee: Chaussain JL. Glycemic response to 24 hour fast in normal children and children with ketotic hypoglycemia. J Pediatr. 1973 Mar;82(3):438-43
OUTCOME
HYPOGLYCAEMIA
Study: 661 Premature newborns
Definition: Blood glucose < 2.6 mmol/l
Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ. 1988 Nov 19;297(6659):1304-8.
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
GLYCOGEN STORAGE DISEASE TYPE 1
Glucose-6-P GlucoseGlucose-6-P
Endoplasmicreticulum
TranslocaseGSD 1b
PhosphataseGSD1a
GLYCOGEN
Glucose-1-P
Pyruvate
Glycolysis
Lactate
GLYCOGEN STORAGE DISEASE TYPE 1
After a short fast marked hypoglycaemiahypoketosislactic acidosis
Untreated may remain asymptomatic with very low blood glucose concentrations
and high lactate
Lesson: Importance of alternative fuels
Treated At risk of severe hypoglycaemia – lactate suppressed
HYPERINSULINAEMIC HYPOGLYCAEMIA IN INFANCY
Inappropriately raise insulin concentrations whilst hypoglycaemic
• Lipolysis and ketogenesis suppressed
• Branched chain aminoacid concentrations low
• Detectable insulin with blood glucose < 3 mmol/l
= no alternative fuel
OUTCOME Always guarded - often poor
• Increased glucose utilisation rate (particularly neonates)
HYPOGLYCAEMIA
Factors affecting outcome
1. Glucose concentration
2. Duration and frequency of hypoglycaemia
3. Diagnosis – presence of an alternative fuel
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.
NEUROLOGICAL CHANGES DURING HYPOGLYCAEMIA
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
MUST HAVE QUICK ANSWER!
• If strip glucose is low, measure glucose in laboratory
and ‘hypoglycaemia screen’
or at least store some plasma frozen
HYPOGLYCAEMIA
TREATMENT
• If co-operative give drink orally
• If not co-operative give glucose 200mg/kg intravenously
Monitor response of blood glucose
HYPOGLYCAEMIA
Aetiology Endocrine
HyperinsulinaemiaAdrenal diseaseGrowth hormone deficiencyHypopituitarism
(Glucagon deficiency)(Catecholamine deficiency)
HYPERINSULINAEMIA IN INFANCY AETIOLOGY
Requires urgent specialist management
Single gene disordersABCC8,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
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 diseaseDefects of gluconeogenesisDisorders of -oxidation and ketogenesisRespiratory chain disorders (involving the liver)Organic acidaemiasTyrosinaemia type 1
(Ketotic hypoglycaemia)
HYPOGLYCAEMIA
Aetiology Others
Severe illness shocksepsissevere malnutrition
Poisoning alcoholinsulinsulphonylureas, etc-blockers
Malaria
INVESTIGATIONS FOR HYPOGLYCAEMIAduring 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 HYPOGLYCAEMIAduring hypoglycaemia (minimum set)
1. Endocrine B U&E, insulin , cortisol
2. Metabolic B glucose, lactate3-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
Insulin undetectable < 2 - 5 mU/l < 25 pmol/l
Cortisol >400 nmol/l
Growth hormone >15 mU/l
RESPONSE TO HYPOGLYCAEMIA
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
2. The fast must be properly supervised
4.The fast must continue long enough
1. Measure blood spot acyl carnitines before fast.
3. The full range of investigations must be completed
Please do not attempt this if these conditions cannot be met.
SUPERVISED FASTS FOR HYPOGLYCAEMIAand SUSPECTED METABOLIC DISEASE
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%)
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.
SUPERVISED FASTS FOR HYPOGLYCAEMIAand SUSPECTED METABOLIC DISEASE
Diagnoses
Hyperinsulinaemia 12Defects of -oxidation /ketogenesis 7Others 11
Total 30
Ketotic hypoglycaemia 32
Note the value of a negative result
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.
SUPERVISED FASTS FOR HYPOGLYCAEMIAand 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.
Specimens from hypoglycaemic episode
? diagnosis
History & exam
explicable : no need to investigate
Further investigations as appropriatesynacthen test, pituitary function tests,Urine organic acids, DNA Mutation analysis, etc.
no
Diagnostic path for recurrent hypoglycaemia in children
no
yes
Possiblediagnosis
? diagnostic clues
yes
Unexplainedwith no clues Next page
To be tested
? FFA/ketone ratio use graph
Disorder of fatty acid oxidationincreased
Ketone body utilisation defectdecreased
normal
?hepatomegalyGlycogen storage disease type III and disorders of phosphorylase cascadeyes
no
“Ketotic hypoglycaemia”Adrenal disorders - see aboveGrowth hormone deficiency in infants
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
KETOTIC HYPOGLYCAEMIA
Recent experimental studies
glucose production rates
Ketone utilisation ?
leucine oxidation rates
glycogenolysis and gluconeogenesis
plasma alanine concentrations
plasma ketones
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.
? 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 fastingresistant to anticonvulsants
• Developmental delay
• Complex movement disorder - speech , ataxia, etc
Diagnosis CSF /blood glucose < 0.4 - 0.46CSF lactate lowmutations in GLUT1 ( heterozygous)RBC glucose uptake studies