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

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

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

HYPOGLYCAEMIA

HOW TO DEFINE

1. Symptoms

2. Outcome

3. Neurological changes

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

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

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

Need to identify cause

HYPOGLYCAEMIA

Aetiology

1. Endocrine

2. Metabolic

3. Hepatic

4. Others

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 Hepatic

Acute liver failure of any cause

Cirrhosis of any cause

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%)



Diagnoses

Hyperinsulinaemia 12Defects of -oxidation /ketogenesis 7Others 11

Total 30

Ketotic hypoglycaemia 32

Note the value of a negative result



Diagnostic yield if

Documented hypoglycaemia 22/79 (28%)

Only suspected hypoglycaemia 1/30 ( 3%)


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

hypoglycaemia in infancy and childhood practical advice j v leonard ucl institute of child health,...

Documents