Inborn Errors of Metabolism in the Emergency Department. Will Davies June 2014

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1 Inborn Errors of Metabolism in the Emergency Department Will Davies June 2014

2 Inborn Errors of Metabolism in the Emergency Department Overview Although individually rare, altogether they are 1: incidence. Broadly Defined: An inherent deficiency in a key metabolic pathway resulting in Cellular intoxication Energy deprivation Mixture of the two Presentation: Acute life threatening illness encephalopathy - lethargy, irritability, coma vomiting respiratory distress Seizures, Hypertonia Hepatomegaly (enlarged liver) Hepatic dysfunction / jaundice Odour, Dysmorphism, FTT (failure to thrive), Hiccoughs Assessment: Bloods: ABG-acidosis, U&Es, Ca and LFTs, NH 4, Lactate, Pyruvate, FBC, Coags- PT/PTT UA-ketones, urine reducing substances, hold for OA/AAs Newborn screen results LP- r/o Meningitis, but send lactate STAT, hold tubes for future Drug toxicology screen if indicated. Hold spun blood or urine sample in fridge for later if possible

3 ABG, Lactate are iced STAT samples NH4 should be free flowing, arterial sample sent straight to lab on ice with lab pre-warned Management in ED Correct hypotension Nil by mouth Reverse catabolism with 5% dextrose in half normal saline at maintenance. Correct hypoglycaemia with 10% dextrose in neonate and 25% in infants, target BSL 6-9mmol/L. Correct metabolic acidosis (ph< 7.2) slowly (Sodium bicarbonate: meq/kg/h (up to 1-2 meq/kg/h) IV; if intractable acidosis, consider haemodialysis) Avoid hypotonic fluids if NH4 high Avoid Hartmanns Dialysis, lactulose if high/toxic NH 4 Search for and treat precipitants; ie: infection, dehydration. Low threshold for sepsis work up and Abx if uncertain. Pyridoxine 100 mg I.V. for neonatal seizures which are unresponsive to normal anti-epileptic medications.

4 Inborn Errors of Metabolism First used in Croonian Lecture RCP London 1908 Sir Archibald Garrod Son of Sir Alfred Baring Garrod Father of inborn errors of metabolism

5 Garrod Hypothesis Or one gene-one enzyme hypothesis Single point mutation in a gene can give rise to a change in enzyme activity and hence a failure or change in pathway of metabolism

6 Garrod s hypothesis Substrate Excess Product Deficiency A B C D Toxic Metabolite

7 Confirmation and Refinement One gene-one polypeptide Edward Tatum Genetic Control of Biochemical Reactions in Neurospora. G. W. Beadle and E. L. Tatum. Proc Natl Acad Sci U S A. Nov 15, 1941; 27(11): George Beadle

8 Substrate Excess Product Deficiency A B C Product may be energy D Toxic Metabolite

9 Examples Disorders that result in toxic accumulation Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects) Disorders of carbohydrate intolerance Lysosomal storage disorders Disorders of energy production, utilization Fatty acid oxidation defects Disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis) Mitochondrial disorders

10 Epidemiology. Racial Prevalence Genetic origin and wide diversity of disease means variable epidemiology with ethnicity eg: CF 1:1600 European Sickle cell 1:600 west African Tay Sachs Disease 1:3500 Ashkenazi Jews G-6-PD deficiency 70% Kurdish Jews Overall around 1:1000-1:2500 live births

11 Epidemiology. Age Age for presentation of clinical symptoms varies for individual inborn errors of metabolism (IEM) and variant forms within the IEM. The timing of presentation depends on significant accumulation of toxic metabolites or on the deficiency of substrate. The onset and severity may be triggered by environmental factors eg. dietary change, intercurrent illness or other stressors. Disorders of protein or carbohydrate intolerance and disorders of energy production will present in the neonatal period or early infancy.. Fatty acid oxidation defects, glycogen storage, and lysosomal storage disorders tend to present in infancy or childhood. Disorders are often manifested by subtle neurologic or psychiatric features and are often missed.

12 Screening Australia and NZ have a comprehensive screening of neonates. 99% parents consent. DBS genetic screening very specific. 31 IEMs screened for.

13 Genetic testing introduced in NSW in 1998 led to an increase in detection. Screening Newborns for Inborn Errors of Metabolism by Tandem Mass Spectrometry. Wilcken et al. n engl j med. 348;23

14 How to Spot em Memorise this lot then do loads of tests?

15 Or. Have a high index of suspicion, particularly in the sick neonate. Take a good history. Do a thorough examination. Do some basic screening tests. Treat the life threatening metabolic emergency. Refer on to a specialist in this sort of thing.

16 Presentation A function of: Age Which IEM Intercurrent metabolic stressor

17 How do metabolic diseases present in the neonate? Acute life threatening illness encephalopathy - lethargy, irritability, coma vomiting respiratory distress Seizures, Hypertonia. Hepatomegaly (enlarged liver). Hepatic dysfunction / jaundice. Odour, Dysmorphism, FTT (failure to thrive), hiccups.

18 How do you recognise a metabolic disorder?? Index of suspicion eg with any full-term infant who has no antecedent maternal fever or PROM (premature rupture of the membranes) and who is sick enough to warrant a blood culture or LP, one should proceed with a few simple lab tests. Simple laboratory tests Glucose, Electrolytes, ABG, Ketones, urea, Creatinine Lactate, Ammonia, Bilirubin, LFT

19 Index of suspicion Family History Most IEM s are recessive - a negative family history is not reassuring! CONSANGUINITY, ethnicity, inbreeding neonatal deaths, fetal losses maternal family history males - X-linked disorders all - mitochondrial DNA is maternally inherited A positive family history may be helpful!

20 Index of suspicion History CAN YOU EXPLAIN THE SYMPTOMS? Timing of onset of symptoms After feeds were started? Any specific food triggers? With intercurrent infection? Response to therapies

21 Index of suspicion Physical examination General dysmorphisms (abnormality in shape or size), ODOUR Eyes - cataracts, retinitis pigmentosa CNS - tone, seizures, tense fontanelle Resp - Kussmaul s, tachypnea CVS - myocardial dysfunction Abdo - HEPATOMEGALY Skin - jaundice

22 Index of suspicion Laboratory ANION GAP METABOLIC ACIDOSIS Normal anion gap metabolic acidosis Respiratory alkalosis Low BUN relative to creatinine Hypoglycemia especially with hepatomegaly non-ketotic

23 Laboratory Tests Disease Non-ketotic hyperglycinaemia Urea cycle defects Fatty acid oxidation defects Organic acidaemias Carbohydrate metabolism disorders Amino acidurias Glycogen storage disorders Metabolic Acidosis Absent Absent or mild lactic Mild acidosis Severe with high anion gap Present Present Lactic acidosis Ammonia Normal High with low Urea High High or normal Normal Normal or high Normal Glucose Normal Normal Very low Low or normal Very low Low Very low Other laboratory Elevated glycine No ketonuria Elevated LFTs Ketonuria Low WCC Low Plts Raised bilirubin Urinary amino acids Hyperlipidaemia Clinical association Uncontrolled hiccups Hypotonia Seizures Emesis Lethargy Coma Hepatomegaly Coma First 2-7 days of life Appear drunk?gram ve sepsis Coincides with first milk Increased tone Sweet body odour Hepatomegaly +/- severe cardiomegaly

24 Overview Management in ED Can be life threatening event requiring rapid simultaneous assessment and management. ABC s and treat threats as as found

25 Investigations to Get During Assessment ABG-acidosis U&Es, Ca and LFTs NH4 Lactate, Pyruvate FBC Coags- PT/PTT UA-ketones, urine reducing substances, hold for OA/AAs Newborn screen results LP- r/o Meningitis, but send lactate STAT, hold tubes for future Drug tox screen if indicated. **Hold spun blood or urine sample in fridge for later if possible. **ABG, Lactate are iced STAT samples ** NH4 should be free flowing, arterial sample sent straight to lab on ice with lab prepared for it.

26 Management Correct hypotension Nil by mouth Reverse catabolism with 5% dextrose in half normal saline at maintenance. Correct hypoglycaemia with 10% dextrose in neonate and 25% in infants, target BSL 6-9mmol/L. Correct metabolic acidosis (ph< 7.2) slowly (Sodium bicarbonate: meq/kg/h (up to 1-2 meq/kg/h) IV; if intractable acidosis, consider haemodialysis) Avoid hypotonic fluids if NH 4 high Avoid Hartmanns

27 Management Dialysis, lactulose if high/toxic NH 4 Search for and treat precipitants; ie: infection, dehydration. Low threshold for sepsis work up and Abx if uncertain. Pyridoxine 100 mg IVfor neonatal seizures that are unresponsive to normal anti-epileptic medications.

28 Disposition Paediatric/neonatal HDU/ICU depending on clinical state. Must have experience in IEM

29 Thank You Easy Questions?

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