1. HYPOGLYCAEMIA IN INFANCY AND CHILDHOOD Practical advice J V Leonard UCL Institute of Child Health, London

2. 1. Acute illness 2. Long term complications – mental retardation 3. Genetic implications IMPORTANCE OF HYPOGLYCAEMIA

3. HYPOGLYCAEMIA ‘STANDARD’ DEFINITION Blood glucose < 2 (or 2.2) mmol/l

4. HYPOGLYCAEMIA HOW TO DEFINE 1. Symptoms 2. Outcome 3. Neurological changes

5. HYPOGLYCAEMIC SYMPTOMS Catecholamine induced Anxiety Sweating Palpitations Pallor Tremulousness Weakness Hunger Abdominal pain Nausea/vomiting Neuroglycopenia 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

6. 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

7. GLYCOGEN STORAGE DISEASE TYPE 1 Glucose-6-P GlucoseGlucose-6-P Endoplasmic reticulum Translocase GSD 1b Phosphatase GSD1a GLYCOGEN Glucose-1-P Pyruvate Glycolysis Lactate

8. GLYCOGEN STORAGE DISEASE TYPE 1 After a short fast marked hypoglycaemia hypoketosis lactic acidosis Untreatedmay remain asymptomatic with very low blood glucose concentrations and high lactate Lesson:Importance of alternative fuels TreatedAt risk of severe hypoglycaemia – lactate suppressed

9. 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)

10. HYPOGLYCAEMIA Factors affecting outcome 1. Glucose concentration 2. Duration and frequency of hypoglycaemia 3. Diagnosis – presence of an alternative fuel

11. HYPOGLYCAEMIA HOW TO DEFINE 1. Symptoms 2. Outcome 3. Neurological changes

12. 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

13. HYPOGLYCAEMIA Current definition< 2.6 mmol/l

14. HYPOGLYCAEMIA Clinical diagnosis Any very sick child Undiagnosed seizures even if labelled as a ‘febrile convulsion’ Any unexplained recurrent symptoms

15. 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

16. 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

17. HYPOGLYCAEMIA TREATMENT If co-operative give drink orally If not co-operative give glucose 200mg/kg intravenously Monitor response of blood glucose

18. HYPOGLYCAEMIA Need to identify cause

19. HYPOGLYCAEMIA Aetiology 1. Endocrine 2. Metabolic 3. Hepatic 4. Others

20. HYPOGLYCAEMIA AetiologyEndocrine Hyperinsulinaemia Adrenal disease Growth hormone deficiency Hypopituitarism (Glucagon deficiency) (Catecholamine deficiency)

21. HYPERINSULINAEMIA IN INFANCY AETIOLOGY Requires urgent specialist management 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 Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child. 2009 Jun;94(6):450-7.

22. HYPOGLYCAEMIA AetiologyMetabolic Glycogen storage disease Defects of gluconeogenesis Disorders of  -oxidation and ketogenesis Respiratory chain disorders (involving the liver) Organic acidaemias Tyrosinaemia type 1 (Ketotic hypoglycaemia)

23. HYPOGLYCAEMIA AetiologyHepatic Acute liver failure of any cause Cirrhosis of any cause

24. HYPOGLYCAEMIA AetiologyOthers Severe illnessshock sepsis severe malnutrition Poisoning alcohol insulin sulphonylureas, etc  -blockers Malaria

25. INVESTIGATIONS FOR HYPOGLYCAEMIA during hypoglycaemia 1. EndocrineBU&E, insulin (C-peptide), cortisol (GH, glucagon) 2. MetabolicBglucose, lactate (pyruvate), (ammonia) 3-hydroxybutyrate (acetoacetate) free fatty acids, acyl carnitines, free and total carnitine Uketones, organic acids 3. HepaticBLFTs, clotting 4. OthersB/UToxicology, ethyl alcohol, etc B = blood or plasma U = urine

26. ESSENTIAL INVESTIGATIONS FOR HYPOGLYCAEMIA during hypoglycaemia (minimum set) 1. EndocrineBU&E, insulin, cortisol 2. MetabolicBglucose, lactate 3-hydroxybutyrate free fatty acids, acyl carnitines, Uketones, organic acids 3. HepaticBLFTs, clotting 4. OthersB/UToxicology ( if indicated) B = blood or plasma U = urine

27. INVESTIGATION OF HYPOGLYCAEMIA Supervised fasts if no samples or hypoglycaemia suspected for1. Diagnosis 2. Management

28. 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.

29. 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.

30. SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED METABOLIC DISEASE Total fasts138 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.

31. SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED METABOLIC DISEASE Diagnoses Hyperinsulinaemia12 Defects of  -oxidation /ketogenesis 7 Others11 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.

32. SUPERVISED FASTS FOR HYPOGLYCAEMIA and SUSPECTED METABOLIC DISEASE Diagnostic yield if Documented hypoglycaemia22/79 (28%) Only suspected hypoglycaemia1/30 ( 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.

33. Specimens from hypoglycaemic episode ? diagnosis History & exam explicable : no need to investigate Further investigations as appropriate synacthen test, pituitary function tests, Urine organic acids, DNA Mutation analysis, etc. no Diagnostic path for recurrent hypoglycaemia in children no yes Possible diagnosis ? diagnostic clues yes Unexplained with no clues Next page To be tested

34. Blood spot acyl carnitines Diagnostic fast ? Diagnosis no Unexplained with no clues Abnormal acyl carnitines normal Next page yes Further investigations as appropriate synacthen test, pituitary function tests, Urine organic acids, DNA Mutation analysis, etc.

35. ? hypoglycaemia BS < 2.6 mmol/l ? Detectable insulin Plasma insulin >5 mU/l yes ? C-peptide detectable Exogenous insulin no Next page If FFA > 1 mmol/l may still be useful diagnostic information Diagnostic fast no yes Hyperinsulinaemia note FFA,ketones low and in neonates cortisol also yes no

36. ? Cortisol <200 nmol/l yes no Adrenal disease Hypopituitarism Next page ? Growth hormone < 15 mU/l Check height velocity ? low Glucagon test ACTH, etc ? Raised blood lactate during fast > 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 noyes no yes

37. ? FFA/ketone ratio use graph Disorder of fatty acid oxidationincreased Ketone body utilisation defectdecreased normal ?hepatomegaly Glycogen storage disease type III and disorders of phosphorylase cascade yes no “Ketotic hypoglycaemia” Adrenal disorders - see above Growth hormone deficiency in infants

38. ? FFA/ketone ratio use graph Disorder of fatty acid oxidationincreased Ketone body utilisation defectdecreased normal ?hepatomegaly Glycogen storage disease type III and disorders of phosphorylase cascade yes no “Ketotic hypoglycaemia” Adrenal disorders - see above Growth hormone deficiency in infants

39. 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

40. 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

41. HYPOGLYCAEMIA IN CHILDREN CONCLUSIONS 1. Hypoglycaemia is an important problem 2. Diagnosis most easily made if correct specimens are collected when hypoglycaemic AND

42. 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 DiagnosisCSF /blood glucose < 0.4 - 0.46 CSF lactate low mutations in GLUT1 ( heterozygous) RBC glucose uptake studies