Management of Metabolic Emergencies

1. By Prof. MANAL ELDEFRAWY Awareness of some IEM 2011 Management of Metabolic Emergencies

2. Objectives • When to suspect a metabolicdisorder? • Immediate investigations • Specific investigations • Which emergency measures? • Diagnostic algorithm • Case presentation

3. Single gene defect in an enzyme or transport protein, which results in a block in a metabolic pathway of proteins ,CHO, fats, or complex molecules. • Effects are due to: toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production caused by a deficiency of products beyond the block, or a combination of these metabolic deviations

4. The incidence, collectively, is estimated to be approximately 1 in 4000 live births The inheritance is mostly autosomal recessive with male to female ratio of 1:1

5. WhenTo think Metabolic Time & Pattern of Onset Neonatal period • Intoxication type Typically born healthy, symptom free period Deterioration with poor feeding, vomiting, lethargy, apnea seizures, coma. e.g. a.acidopathies, Organic acidemia, UCDs , CHO intolerance. B) Energy deficiencies No apparent Symptom free Overwhelming neurologic deterioration apnea, seizures, coma e.g. FAO defects, Mitochondrial disorders, peroxisomal disorders

6. When To Think Metabolic?Beyond neonatal period • Lethargy or just not doing well • Refusal to feed poor suckling • Vomiting • Poor weight gain • Hepatomegaly • Tachypnea • Hypothermia • Axial hypotonia • Limb hypotonia • Abnormal movements(pedalling , tremors) • Altered conscious, seizures, coma • Multivisceral failure

7. When to think metabolic? Additional factors • Consanguinity • Unexplained Neonatal deaths • Unexplained Deterioration with symptomatic treatment

8. Initial investigations parallel to Sepsis screening • Urine • Ketonuria bedside test • Unusual Odour • Unusual colour • Reducing subtances • Blood • Glucose • Electrolytes: Na,K,cl,Ca • Ammonia • Blood gases • Anion gap • Transaminases • Prothrombin T&C & INR • Urea & creatinine • Uric acid • Lactic acid • CK • CBC

9. Second Line Evaluation • Urine and plasma aminogram • Urine organic acid profile by GC-MS • Plasma carnitine and Acylcarnitine profile: Increase carnitine ester in fatty acid oxidation defect, organic academias, ketosis • Dried blood spot analyzed by tandem mass spectrometry (MS/MS).

11. Second Line Evaluation(cont.) • CSF anaylsis NKH is diagnosed by the presence of elevated CSF to plasma glycine ratio Decrease CSF glucose/to blood glucose…..glucose transporter defect • Peroxisomal function Test Plasma very long chain fatty acids (VLCFAS), Phytanic acid, erythrocyte plasmalogen levels • Stored samples Frozen whole and heparinized bl., serum, CSF & urine (store at -20°C).

12. Emergent treatment of IEMs (acute life-threatening ) • Establish airway, breathing, circulation. • Avoid lactated Ringer’s. • Avoid hypotonic fluid load due to the risk of cerebral edema (if hyperammonemia is present). • NPO :Discontinue intake of offending agents; (especially no protein, galactose, or fructose) • Provide adequate glucose to prevent catabolism. (Fluidboluses D10 normal saline).

13. Most IEMs with acute life-threatening presentation can be categorized based on finding of at least 1 of the following : • Hyperammonemia • Metabolic acidosis • Hypoglycemia • Jaundice and Liver dysfunction

14. Hypoglycemia Severe, persistent, without other etiology If with metabolic acidosis e.g. OA, GSD Type 1 , Fructose 1,6Diphosphatase deficiency, FAO (hallmark Non ketotic) N.B :Hypoglycemia (plasma glucose level < 50 mg/dL)

15. Hypoglycemiain neonatal period

16. Treatment ofHypoglycemia • D10 to D15 with electrolytes 8-12 mg/kg/min IV to maintain serum glucose leveat 120–170mg/dL which should prevent catabolism. • High-volume maintenance fluid 1-1.5 times maintenance will also promote urinary excretion of some toxic metabolites. • If necessary, treat hyperglycemia with insulin (0.2-0.3 IU/kg/h) to maintain glucose level in the desired range.

17. Hyperammonemia • Excess ammonia (about80% dietary and waste nitrogen) is converted to urea in the liver through urea cycle. • The five enzymes that make up the urea cycle are regulated long term by the quantity of dietary protein. • Ammonia level : >100 mcg/dL in the neonate > 80 mcg/dL beyond the neonatal period is considered elevated & toxic.

18. Hyperammonemia This can lead to Encephalopathy and death OR Devastating neurological sequelae. Neurological sequelae and survival depend on the length of hyperammonemic coma(better prognosis <36h or<2days).

19. Hyperammonemia • Significant hyperammonemia is observed in • Urea cycle defect • Organic acidemia • Fatty acid oxidations defects • THAN • Ammonia is highest in the UCDs often exceeding 1000 mcg/dL and causing primary respiratory alkalosis sometimes with compensatory metabolic acidosis. • Ammonia in OA, if elevated, rarely exceeds 500 mcg/dL, and in FAO is usually less than 250 mcg/dL.

20. Hyperammonemia Acidosis Normal PH or alkalosis Organic acidemiaPyruvate metabolism Normoglycemia Hypoglycemia Hypoketosis Plasma aminoacids Urea cycle disorders Fatty acid oxidation (FAO) Increased citrulline ASA present Increased Citrulline ASA absent Low/Normal citrulline Urine Orotic acid Citrullinemia Argininosuccinicacidemia OTC deficiency CPS deficiency THAN

21. The therapeutic protocol include : • Avoidance of nitrogen intake by nasogastric infusion of a protein-free formula. • Adequate caloric intake (80-120 kcal/kg/d) by glucose (10 – 20 g/kg ) . • Sodium benzoate (250-500 mg/kg/d),more recently phenylbutyrate(250mg/kg/d) peroral • IV administration of arginine(250-500mg/kg/d) • Carnitine(250-500 kg/d) • Hydroxycobalamin( 1mg/d) • Biotin( 10 mg/d) • Insulinmay be added to utilize its anabolic effect (0.1 -1 IU /kg/ hr if bl. glucose > 200 mg/dl ) • Dialysisin patients not responding to pharmacological therapy

22. Case presentation • A 3 years old boy presented to ER with disturbed level of consciousness of 2 days duration triggered by fever and associated with one brief attack of generalized tonic clonic seizures. • The day before he ate high protein containing food which was followed by : period of hyperirritability and profuse vomiting then gradual and progressive lapse in the level of consciousness which worsen upon the introduction of depakene to control the seizure .

23. Past history : revealed two similar episodes of disturbed conscious level : -The first was at 7days in neonatal period . CT at that time revealed brain edema. -The second episode was at the age of 18 months. • Examination : revealed a semi conscious child with generalized axial and limb hypotonia, RR 50/m.

24. Lab investigation • Blood gases: ph=7.5 , Pco2=24 ,Hco3=18 • Ammonia level =250mg/dl • Lactate = 3.2 mmol/l ( n < 2.1 ) • Normal LFT &KFT • CBC: mild neutrophilia • Salient features • Disturbed conscious level • respiratory alkalosis • Hyperammonemia

25. MS/MS revealed very high level of citrulline • Orotic acid in urine wasincreased • Final diagnosis: citrullinemia

27. MS/MS Normal Citrullinemia

28. HHH syndrome • One year & 1mth old boy with severe failure to thrive , excessive sleepiness . • The condition started at the age of 4mths after feeding baby with yogurt . He started to have recurrent attacks of vomiting sometimes with diarrhea ,admitted to hospital for IV fluids. • On examination: Fair complexion , apathy , GDD (motor &mental) . Normal abd. Exam. Pt . weighted 6 kg , H.C. 42 cm , length 69 cm (all< 3rd percentile for age)

29. HHH syndrome

30. HHH cont. • Investigations: HGB : 10.5 , normocytic,normochromic a. ABG: metabolic alkalosis ( repeatedly) Ammonia : high ( repeatedly) > 300ug/dl TMS: ( HHH syndrome) Hyperammonemia, Hyperornithinemia and Homocitrullinemia

31. HHH syndrome after therapyTreat. hyperammonemiaornithine supplementation ????

32. Metabolic Acidosis • Among the inborn errors, the largest group typically associated with overwhelming metabolic acidosis in infancy is the group of organic acidemias • Methylmalonicacidemia, • Propionicacidemia, and • Isovalericacidemia.

33. Important Laboratory Findings in Organic Acidemia • Hyperlacticacidemia • Neutropenia and thrombocytopenia • Hyperammonemia • Ketosis

35. Emergency management of metabolic Acidosis • Metronidazole(10-20mg/kg) and neomycin (50mg/kg) reduce the level of priopionic acid and methyl malonic acid in body fluid • Antibioticas clindamycin and vancomycin. • Hyperammonemic episodesshould be treated promptly with Na benzoate(250mg/kg in10% glucose) • Aggressive fluid and electrolytetherapy is essential in acute ketoacidotic crisis: 150mg-200mg/kg of 10% glucose and isotonic NAHCO3 until acidosis is corrected: 0.25-0.5 mEq/kg/h (up to 1-2 mEq/kg/h) IV • Consider hemodialysis; if intractable acidosis, (peritoneal dialysis, hemofiltration, exchange transfusion much less effective).

36. Methylmalonic acidemia • Marked failure to thrive • severe metabolic acidosis • ketosis • Severe psychomotor retardation • Encephalopathy • Dystonia • Recurrent seizures • Peritoneal dialysis

37. Brain MRI • T2w MRI demonstrating bilateral and symmetrical high signal intensity lesions in the globuspallidus

38. MMA Date : 9/2010 - 2 years old male -3mths ago he developed recurrent attacks of G.E. & M.A. -Then he suffered from coma for nearly a week ?. -After that he developed severe failure to thrive. Expanded metabolic screen using LC-MS/MS showed MMA

39. Ethyl MalonicAcidemia • A.A, the 3rd child of first degree consanguineous parents whose birth date is 8/2008 • The patient presented at the age of 9 months with GDD and intractable seizures • Antenatal, natal and perinatal period were uneventfull • Clinical exam revealed, microcephaly, microphthalmia, frontal bossing, hypertolerism, epicanthic folds, long filtrum and bat ears

40. Ethyl MalonicAcidemia • Neurological exam revealed hypertonia, hyperreflexia, positive babinski , truncalhypotonia. • Recurrent ecchymotic patches on the lower limb • No episodes of metabolic decompensation or metabolic acidosis • Pt. has a normal 4 years aged sister and mother had one abortion

41. Ethyl MalonicAcidemia • TMS result: • elevated butyrylcarnitine (C4) =4. micomol/L cut off value =1.5 micromol/L • Urine organic acid analysis by GC-MS showed • highly elevated Ethylmalonic acid • and moderately elevated methylsuccinic acid • no dicarboxylicaciduria and • no lactic aciduria

42. Brain MRI in EMA T2w Brain MRI showing widening of extraaxial CSF spaces, and sylvian fissure, picture of severe brain atrophy TW1 Brain MRI showing frontotemporal atrophy

43. Ethyl malonicacidemia • Five mths old girl coming from Gaza(during 25 January revolution 2011) with recurrent attacks of diarrhea, vomiting ,with severe napkin dermatitis and failure to thrive. • Clinical exam. revealed, microcephaly, frontal bossing, hypertolerism, epicanthic folds, long filtrum and bat ears • She weighted 3 kg , she had hyperammonemia , met . acidosis . • TMS : Ethyl malonicacidemia

44. Pyroglutamicaciduria • 3 mths old boy ,1st baby • Admitted to PICU due to DCL , shortness of breath, increased yellowish discoloration of skin after severe attacks of vomiting for previous 2 days not associated by diarrhea.

45. History The condition started at the age of 5 days by Jaundice which was diagnosed as physiological , no treatment . For the following 3 month the mother noticed gradual abd . distention and no improvement in colour . On examination the baby was lethargic with tachypnea , hepatomegaly (span 10cm ) and cholestatic jaundice ( T=9.6 , d=5.2). He was ventilated but it was difficult to be weaned from vent. as he developed cardiac problems as severe bradycardia and arrest.

46. Investigations • CBC: HB 10gm% , WBC :24,000 • Bil total: 9.6 Direct :5.2 mg/dl • ALT :115 . PT :26, INR:2.9 • Urea :30 , creatinine:0.7 • CRP: 12 • ABG : variable with increased anion gap 59 • Bl. Ammonia : 607---- 230---303 ug/dl • MS/MS : Pyroglutamicaciduria • Urineorganic acids was done

47. The baby was treated with Na benzoate and glutathione analogs, vit C and vit E.He started to gain consciousness and he was weaned from the vent. The jaundice and hepatomegaly decreases .

48. Pyroglutamicaciduriaafter therapy

49. 2.8 years old • At the age of 2y , she developed recurrent attacks of convulsions and was treated with antiepileptic drugs • At 2.1 y, she suffered recurrent attacks of RD with metabolic acidosis , no hypogycemia ,no hep. • Then she went in coma for 1 d. • Bl Ammonia level was elevated • so she received Na benzoate • She improved for 2w then amm. increased again. • MS/MS was normal • ALT ,AST were 2-3 times normal • There was no hypoglycemia during • the illness • Liver span 10 cm, firm • Liver biopsy 10/8/2010 • metabolic LD ---- GSD

50. Thank You