HYPOGLYCAEMIA IN INFANCY AND CHILDHOOD Practical advice

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

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

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 Neuroglycopenia Fits Lethargy Confusion Visual disturbances Behaviour disturbance Dysarthria/ ataxia Parasthesiae Headache Focal neurological signs Coma Catecholamine induced Anxiety Sweating Palpitations 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 Mar;82(3):438-43

6. 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.

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

8. 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

9. 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

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. 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.

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 • 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 • If strip glucose is low, measure glucose in laboratory • and ‘hypoglycaemia screen’ • or at least store some plasma frozen MUST HAVE QUICK ANSWER!

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 Aetiology Endocrine Hyperinsulinaemia Adrenal disease Growth hormone deficiency Hypopituitarism (Glucagon deficiency) (Catecholamine deficiency)

21. 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.

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 illness shock sepsis severe malnutrition Poisoning alcohol insulin sulphonylureas, etc b-blockers Malaria

25. 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

26. 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

27. INVESTIGATION OF HYPOGLYCAEMIA Supervised fasts if no samples or hypoglycaemia suspected for 1. Diagnosis 2. Management

28. 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.

29. 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.

30. 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%)

31. 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 12 Defects of -oxidation /ketogenesis 7 Others 11 Total 30 Ketotic hypoglycaemia 32 Note the value of a negative result

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.

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

34. ? FFA/ketone ratio use graph increased Disorder of fatty acid oxidation decreased Ketone body utilisation defect 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

35. 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

36. 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

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

38. 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