Neonatal Guidelines. Chapter 10: Metabolic V Date Revised : January 2017 Ratified 6 th February Date for Review: 1 st of March 2021

Transcription

1 Neonatal Guidelines Chapter 10: Metabolic V Specialty: Neonatal Medicine Revised by: Jean Matthes Date Revised : January 2017 Ratified 6 th February 2017 Approved by: ABMU Joint Perinatal Forum Date for Review: 1 st of March

2 Directorate of Child Health Checklist for Clinical Guidelines being submitted for Approval by ABMU Joint Perinatal Forum Title of Guideline: Name(s) of revising author: Chair of Group or Committee supporting submission: Jean Matthes, Edited by S. Banerjee Neonatal Guideline Group Sujoy Banerjee Issue / Version No: Next Review / Guideline Expiry: Review date: 1 st March 2021 Details of persons included in consultation process: Neonatal Consultants, Neonatal junior doctors, Nursing Managers, Neonatal Pharmacist Brief outline giving reasons for document being submitted for ratification Routine Revision Name of Pharmacist (mandatory if drugs involved): Please list any policies/guidelines this document will supercede: Katherine Willson Chapter 10:Metabolic v2013 Keywords linked to document: Metabolic, neonate Date approved by ABMU Joint Perinatal Forum: 6 th February 2017 File Name: Used to locate where file is stores on hard drive 2

3 CONTENTS Topics Page number Introduction to IEM 4 Clinical presentation 4 Clinical Examination 6 Initial screen for metabolic disease 9 Further investigations for specific conditions 11 Treatment general principles 13 Treatment of hyperammonaemia 13 Some specific disorders 15 Notes on specimens 22 3

4 Inborn errors of metabolism Introduction: Inborn errors of metabolism (IEM) are individually rare. Some conditions may only be seen once in a professional s working life. But there are very many different conditions so their combined incidence is significant. Usually a high index of suspicion is required to make the diagnosis. Early detection and treatment may prevent lifelong neurological damage. Early discussions with the newborn screening laboratory in UHW may ensure that the correct investigations are taken and processed urgently rather than routinely, saving valuable time. Likewise a discussion with our biochemistry laboratory in ABMU is required to ensure that samples are sent to Cardiff expeditiously. These discussions are best undertaken consultant to consultant. A very useful Website for investigation and treatment of metabolic conditions is BIMDG the British inherited metabolic diseases group. This also covers what interim treatment may be given to a newborn infant who may have a disorder, whilst awaiting the results of the diagnostic tests. It also gives treatment regimens for specific conditions. Please refer to this site when implementing emergency treatment. Newborn screening is undertaken in Wales for glutaric aciduria, homocysteinuria, isovaleric acidaemia, maple syrup urine disease, phenylketonuria and medium chain acyl CoA dehydrogenase deficiency. These tests are done on the 5 day heel prick Guthrie test but the result may not routinely be available until the child is several weeks old. Earlier diagnosis is definitely beneficial. So if you suspect one of these disorders, do not wait for the routine Guthrie to be reported. Contact the laboratory and expedite the test! Metabolic conditions may present in the following ways Antenatally suspected: babies born to mothers with acute fatty liver of pregnancy [AFLP], or to mothers with recurrent HELLP syndrome [haemolysis, elevated liver enzymes and low platelets] are at increased risk of LCHAD. Abnormalities evident at birth: dysmorphic features, severe hypotonia, seizures and apnoea, hydrops and ascites. 4

5 Presentation following an asymptomatic interval [of varying lengths hours to weeks]. Presentation may be non-specific, and may mimic sepsis. a. Encephalopathy: poor feeding, persistent vomiting with no anatomical cause, persistent hiccups, seizures, coma. b. Acid-base disturbance c. Liver impairment d. Cardiac impairment e. Unexplained hypoglycaemia f. Hyperammonaemia g. Others: Unusual odours, Cataract, Neutropenia, Thrombocytopenia Other clues from the history. a. Parental consanguinity b. Previous neonatal death c. Recurrent non-immune hydrops fetalis d. Siblings with known inborn errors of metabolism In the work up of a baby presenting with any of the above, IEMs should be considered in the differential diagnosis. Therefore, in addition to any other investigations requested, a set of preliminary tests should be sent aiming to identify the presence of an IEM. Pathogenesis: Majority are autosomal recessive. A few are X-linked recessive, e.g. ornithine carbamyl transferase (OCT) deficiency. a) Problems making and breaking complex molecules. Making: Breaking: Zellweger Inability to synthesise peroxisomes Smith Lemli Opitz block in cholesterol synthesis CDG (congenital disorders of glycosylation) block in glycosylation Hurler Syndrome failure to breakdown mucopolysaccharides Tay Sachs failure to breakdown gangliosides Fabry disease failure to breakdown glycolipids 5

6 b) Intoxication: Urea cycle disorders block in ammonia clearance Organic acidaemias block in amino acid breakdown Galactosaemia block in Galactose metabolism c) Energy Insufficiency: Congenital lactic acidosis Respiratory chain disorders (mitochondrial disorders) Pyruvate metabolism disorders Energy supply - Fat oxidation defects (FAO) Glycogen storage disorders (GSD) Gluconeogenesis defect d) Deficiencies of glucose transporter enzymes (e.g. GLUT1) Clinical Examination: A careful clinical examination of all the systems is required. These include:- Dysmorphic features Cardiovascular system, especially tachycardia, capillary refill time, signs of cardiac failure. Respiratory - especially respiratory rate in metabolic acidosis, apnoea in altered conscious state. GIT - jaundice, hepatomegaly, splenomegaly. Neurological - conscious level, seizures, abnormal movements, tone, posture, irritability, feel the fontanel, measure the head circumference. Urinalysis glucose and ketones. Smell. Eyes look carefully for cataracts, corneal clouding. Fundus for pigment or cherry red spot. 6

7 Clinical Presentation and Differential Diagnosis Seizures: When the usual causes of HIE, infection and biochemical causes have been excluded or seem unlikely, metabolic causes need to be considered. a) Isolated Seizures - Pyridoxine dependent seizures - Folinic acid responsive seizures - Biotin responsive multicarboxylase deficiency - Congenital malabsorption of magnesium b) Seizures with other Severe Neurological Signs - Non-ketotic hyperglycinaemia - Sulfite oxidase deficiency - Peroxisomal disorders - GLUT1 deficiency c) Seizures with pre-existing stupor, coma or hypoglycaemia - MSUD - Organic acidaemia - Urea cycle disorder Hypotonia: The most severe metabolic causes of hypotonia are:- - Congenital lactic acidosis - Respiratory chain disorders - Urea cycle disorders - Non ketotic hyperglycinaemia (NKH) - Sulphite oxidase (SO) Deficiency - Peroxisomal disorders Hepatic Presentation: a) Hepatomegaly and seizures suggest:- - Glycogen storage Type I or III 7

8 - Gluconeogenesis defects - Severe hyperinsulinism b) Liver Failure - Galactosaemia - Tyrosinaemia type 1 - Neonatal haemochromatosis - Respiratory chain disorders c) Cholestatic jaundice and failure to thrive - Alpha-1-antitrypsin deficiency - Inborn errors of bile acid metabolism - Peroxisomal disorders - Niemann Pick Type C disease - CDG syndrome - Cholesterol Biosynthesis Defects d) Hepatosplenomegaly - Lysosomal storage disorder Cardiac Presentation: a) Cardiac failure, Cardiomyopathy, Hypotonia and muscle weakness suggests:- - Respiratory chain disorders - Pompe disease - Fatty acid oxidation disorders b) Cardiac failure, pericardial effusions, cardiac tamponade, Cardiomyopathy - CDG syndrome c) Cardiomyopathy and conduction defects - Long chain fatty acid disorders 8

9 Initial screen for metabolic diseases: Unless one is looking for a specific condition (for example when there is a known positive family history), the following test must ALL be undertaken in an initial screen for metabolic disease. Blood gas Metabolic acidosis: organic acidemias, primary lactic acidosis, following collapse in any IEM (even urea cycle disorders!) Respiratory alkalosis: seen early in urea cycle defects Electrolytes, urea & creatinine Low urea in relation to creatinine early in urea cycle defects Calculate anion gap [Na + + K + ] [Cl - + HCO - 3 ]: increased > 20 in organic acidemias, primary lactic acidosis, some fatty acid oxidation defects Laboratory blood glucose (Unexplained hypoglycaemia): Hypoglycaemia in babies may accompany the following disorders fatty acid oxidation defects organic acidemias primary lactic acidosis glycogen storage disorders Endocrine causes eg cortisol deficiency, growth hormone deficiency, hyperinsulinaemia Liver enzymes, including albumin, and split bilirubin Elevated liver enzymes and bilirubin are found in : Galactosemia, Tyrosinaemia, peroxisomal disorders eg refsum s disease Full blood count and film Pancytopaenia: in secondary infection or overwhelming disease, which may complicate IEM. Ammonia <180mmol/L may be seen in any severe illness, but must consider IEM 9

10 >200mmol/L: IEM until proven otherwise: urea cycle disorders, organic acidemias, fatty acid oxidation defects, transient hyperammonemia of the newborn. NB emergency treatment of hyperammonemia in section Lactate Persisting >3mmol/L: primary lactic acidosis Beware of sampling errors best if free flowing arterial sample Exclude tissue hypoxia, congestive heart failure, sepsis, post convulsion CPK Urine Ketones: elevated in maple syrup urine disease (MSUD), absent in fatty acid oxidation defects (especially important when absent in presence of hypoglycaemia), Galactosemia, fructose 1,6 biphosphate aldolase deficiency Reducing substances Organic & amino acid profile: Further investigations Recurrent hypoglycaemia See Endocrine Chapter (Special investigations in hypoglycaemia) Do not delay correcting the low blood glucose if the blood is difficult to obtain and do not wait for the urine to be collected. Give 10% glucose 3mls / kg and increase the infusion rate from the baseline. Recheck the glucose within minutes and again at 1 hour Further investigations of raised ammonia (Discuss with lab urgently) U and E, Clotting, Glucose, lactate, blood gas Plasma amino acids requested. Blood spot acyl carnitine profile Urine amino acids Urine organic acids including orotic acid Ammonia >250 micromol/litre - start immediate treatment and arrange transfer to a specialist centre Monitor neurological status (Glasgow coma score or similar for infant) 10

11 Further Investigations according to clinical presentation. (Many of these tests will be done only in specialist centres) Presentation Condition Specific Investigation Encephalopathy Urea cycle defects Organic acidemias & MSUD Urine amino acids Urine organic acids Plasma amino acids Blood carnitine & acylcarnitines Fatty acid oxidation defects Primary lactic acidosis (e.g. puruvate dehydrogenase deficiency, respiratory chain defects) Non-ketotic hyperglycinaemia As above, plus: Blood for DNA mutation analysis CSF Lactate Mitochondrial DNA (blood & muscle) Muscle biopsy (histology & electron microscopy) Skin biopsy (enzymes of pyruvate metabolism) Plasma & CSF amino acids CSF: plasma glycine levels USS brain +/-MRI (agenesis corpus callosum, cerebellar abnormalities Molybdenum cofactor deficiency Pyridoxine dependent seizures Urine sulphite Urine amino acids ( hypoxanthine and taurine) Plasma and urine uric acid Pipecolic acid in plasma and CSF Trial of pyridoxine under EEG Liver Disorders Peroxisomal disorders Glycogen storage disease (types I, III, VI, IXX) Galactosaemia Blood VLCFA Leucocyte / liver biopsy (enzyme assay) Plasma lactate, CPK, uric acid Most diagnosed now on a specific genetic panel Red cell galactose-1-phosphate uridyl transferase activity If recently transfused, above test unreliable, so measure RBC galactose 1 phosphate as alternative ( ) Ophthalmology: for cataracts 11

12 Tyrosinaemia type I Plasma amino acids Urine organic acids Coagulation Investigate for renal Fanconi s syndrome α 1 Antitrypsin deficiency Serum α 1 antitrypsin genotype Niemann-Pick A Acid sphingomyelinase in leukocytes ( ) ( ) HDL cholesterol and cholesterol and TG Foam cells on histiocytes in bone marrow Cardiomyopathy Mitochondrial defects (respiratory chain) Pompe s disease (GSD type II) Fatty oxidation defects Mitochondrial defects CDG 1a syndrome Lysosomal storage disorders CSF lactate Mitochondrial DNA (blood & muscle) Muscle biopsy (histology & electron microscopy) Lymphocyte / skin fibroblast (enzyme assay) As stated under encephalopathy As stated under liver disease Serum transferrin isoelectric focusing Dysmorphism Lysosomal storage disorders Disorders of sterol synthesis CDG (Congenital disorders of glycosylation) syndrome Glutaric aciduria type II Peroxisomal disorders (e.g. Zellweger) Skin biopsy (enzyme assay) White cell enzymes Urine oligosaccharides and mucopolysaccharides as in cardiomyopathy Urine organic acids Plasma 7-dehydrocholesterol Skin biopsy Serum transferrin isoelectric focusing Skin biopsy (enzyme assay) Urine organic acids Blood carnitine & acylcarnitine, VLFA 12

13 **There are also a variety of specialist investigations done, e.g., specific enzyme studies on blood or skin fibroblast, muscle biopsies, etc It is good practice to save and freeze all urine passed for future analysis, and to save a heparinised blood sample before the first blood transfusion. General treatment Acute: This must be commenced as soon as preliminary results suggest a possibility of IEM. Please see website of BIMDG emergency treatment guidelines for further details ABC: basic neonatal intensive care Discontinue all milk feeds Protein content increases amino acid load; toxic in urea cycle defects and organic acidemias. Carbohydrate load contains lactose. Galactose is toxic in Galactosemia Provide adequate calories high calorie, protein free nutrition parenterally, or enterally if specific diagnosis has been made and feeds are judged safe. Correct hypoglycaemia; consider insertion of central access (UVC) early on. Correct acidosis beware of hypernatremia if many NaHCO 3 corrections are given Correct electrolyte disturbances Be vigilant for sepsis; note that some IEMs predispose to sepsis, e.g. galactosemia Insulin for reinforcement of anabolism (dose u/kg/hr) may be considered Liaise with Specialist team early: Dr Graham Shortland Consultant in Metabolic Diseases at UHW if in doubt. Treatment of Hyperammonaemia: Metabolic UHW, led by Dr Graham Shortland, recommend early contact for advice. Remember NH3 is very neurotoxic and needs to be reduced quickly. NH3 > 250 needs the following to commence ASAP, as well as contacting Metabolic team. NH3 > 450 should have haemofiltration - i.e. urgent transfer to PICU. 13

14 (a) Increase glucose infusion rate (GIR) to 7-8mg/Kg/min, even when glucose measurements are normal, and if necessary add insulin if hyperglycemia ensues. This serves to inhibit catabolism of endogenous protein (b) Treat any acidosis / electrolyte imbalance (c) Sodium Benzoate 250mg/Kg IV bolus over 90 minutes, followed by 250mg/Kg over 24 hours as continuous IVI. Together with: (d) Sodium Phenylbutyrate 250mg/Kg IV bolus over 90 minutes, followed by 250mg/Kg over 24 hours as IVI. (e) L-Arginine 200mg/Kg IV bolus over 90 minutes, followed by 8mg/Kg/hour IVI (All the above three drugs are now stocked and available from Singleton NICU If not in stock or out of date contact on call pharmacist) (f) Re-check NH3 four hours after onset of steps (c) to (e), to check for response. Some Specific Disorders Only a few of the more common disorders are covered here in minimal detail. For all of these disorders please refer to the referenced texts and to the BIMDG emergency guidelines for management Glycine encephalopathy (non ketotic hyperglycinaemia) - Basic defect is the glycine cleavage system - Reduced fetal movements in utero - Neonatal disease usually presents early, within 48 hours after birth - Hiccups - Hypotonia - Depressed level of consciousness - Seizures with burst suppression pattern on EEG - Plasma glycine levels variable - CSF and urine glycine are elevated - Organic acids in urine are normal - May be agenesis of corpus callosum - Diagnosis confirmed on transformed lymphocytes or liver biopsy 14

15 Maple Syrup Urine Disease: - Presents at around 1 week of age - Seizures - Encephalopathy - Vomiting - Frequent hypoglycaemia - Severe keto-acidosis and increased anion gap - Typical sweet odour in urine - Elevated leucine, isoleucine and valine in blood and urine Tyrosinaemia Type 1: Type 1 is due to a deficiency of fumaryl acetoacetase (FAH). This causes a build up of fumaryl and maleyl acetoacetate, responsible for renal and hepatic damage. - Progressive liver disease and renal tubular dysfunction - Hypoglycaemia due to pancreatic islet cell hyperplasia - Plasma tyrosine and methionine are raised - Phosphate and potassium levels are low - Generalised aminoaciduria, glycosuria, phosphaturia, rickets - Urinary organic acid increase succinyl acetone Treatment: NTBC 2 (2 nitro 4 trifluoro methylbenzoyl 1, 3 cyclohexanedione). NTBC inhibits hydroxy phenylpyruvate dioxygenase, so reducing toxic metabolites. 15

16 Pathway for Degradation of Tyrosine: Hyperammonaemia differential diagnosis: Inherited disorders - Urea cycle disorders - Organic acidemias (e.g. propionic acidaemia, methylmalonic acidaemia, etc) - Fatty acid oxidation disorders - Other inborn errors (ornithine amino transferase deficiency, HHH syndrome, etc) Acquired disorders - Transient Hyperammonaemia - Perinatal asphyxia - Herpes simplex infection - Liver disease - Any severe illness 16

17 UREA CYCLE DISORDERS: The urea cycle is a metabolic pathway enabling detoxification of ammonia and producing urea. Incidence : OTC (ornithine transcarbamylase), ASS (arginosuccinic acid synthetase) deficiency, ASL (arginosuccinic acid Lyase) deficiency, ARG (arginase deficiency), and NAGs (N acetyl glutamate synthetase) CPS (carbamyl phosphate synthetase) each have incidence of 1:100,000 approx.. Symptoms: Vomiting, drowsiness becoming unconscious, seizures, shock, hepatomegaly Diagnosis: Raised ammonia (>200 µmol/l) Plasma glutamine > 800 µmol/l Normal urinary organic acid profile. Remember to check LFT s, glucose, ammonia and clotting, frequently. 17

18 Early metabolic alkalosis, but can have metabolic acidosis after collapse Treatment please see page 14 Organic Acid Disorders: a) Propionic acidaemia Poor feeding, vomiting, drowsiness, coma Diagnosis Raised ammonia Ketoacidosis Hyperglycinaemia Raised urine organic acid and ketones Increased anion gap Long Term Treatment High carbohydrate Protein restriction Sodium bicarbonate Sodium benzoate Carnitine mg/kg/day b) Methyl Malonic Acidaemia: Clinically similar to proprionic acidaemia. Presents with vomiting, acidosis and neurological depression. Treatment: Withdraw protein, high carbohydrate ± insulin Vitamin B 12 Biotin Galactosaemia This presents after a few days with vomiting, failure to thrive, jaundice, neurological sequelae and possibly a superadded septicaemia, e.g. E. coli, which often starts as a UTI. There is usually hepatomegaly and may be cataracts. If suspected, take urine for reducing 18

19 substances and blood (lithium heparin) for erythrocyte galactose 1 phosphate uridyl transferase. If the baby has previously received a blood transfusion, enzyme analysis is unreliable and diagnosis is achieved measuring Galactose 1 phosphate in blood. Treatment: Stop all lactose and Galactose in diet. Give Nutramigen milk. Lactic Acidosis: In neonates, lactic acidosis is usually secondary to tissue hypoxia, and is not usually associated with ketosis. Increased Lactate is raised in a number of inborn errors a) Respiratory Chain (mitochondrial) Disease Encephalopathy Hypotonia ± Hypoglycaemia Possible Cardiomyopathy Changes in basal ganglia and brain stem on MRI. Also have raised CSF lactate. b) Fructose 1-6 bisphosphatase Deficiency Severe anion gap metabolic acidosis presenting in first week of life A defect in gluconeogenesis pathway Muscle weakness, hepatomegaly Hyperventilation. Hypoglycaemia. Apnea and possible death. High alanine, lactate and pyruvate Diagnosis established by genetic testing Avoid fasting and give dextrose infusion. 19

20 c) Pyruvate Dehydrogenase Deficiency Encephalopathy Hypotonia Severe acidosis increased pyruvate and lactate and alanine Patients deteriorate when given a high glucose intake. May improve if given high doses of thiamine. Need a high lipid, high protein, low carbohydrate regime (ketogenic diet). d) Organic acidaemia ( eg methylmalonic, proprionic, isovaleric, and glutaric type 1 acidemia e) Glycogen Storage Disease (GSD) Type 1: Presents with: Profound hypoglycaemia Lactic acidosis Hyperuricaemia Hyperlipidaemia Hepatomegaly Patients with Type 1b also have chronic Neutropenia with functional deficiencies of neutrophils and monocytes, which required GMCSF therapy. f) Fatty Acid Oxidation Defects: - A number of enzyme defects have been identified enzymes have specificity based on length of carbon chain. - Medium chain acyl co A dehydrogenase (MCAD) deficiency is most common in Caucasians. - Usually presents with hypoketotic hypoglycaemia - Some can cause Cardiomyopathy - May have increased CPK, and transaminases - Characteristic pattern of urine organic acids - Blood spots on Guthrie for acyl carnitine analysis by tandem mass spectrometry 20

21 Peroxisomal Disorders: - Zellweger s Syndrome, Infantile Refsums Disease, neonatal adrenoleukodystrophy - Raised liver enzymes - Dysmorphic - Severe neurological abnormalities plus punctate epiphyseal calcification, liver fibrosis - Request analysis of very long chain fatty acids Further reading 1. Text book Pediatric endocrinology and inborn errors of metabolism K Sarafoglou 2. Text book Atlas of metabolic diseases WL Nyhan, BA Barshop, PT Ozand 21

22 NOTES ON SPECIMENS BIOCHEMISTRY SINGLETON: MORRISTON: MEDICAL MORRISTON: Any sample that needs to be processed outside Swansea, is transported by the biochemists to the Morriston lab first. Some assays require the sample to be frozen as soon it reaches the lab. If a frozen sample needs to be transferred to UHW, this requires special transport, which is routinely available only twice a month from Morriston, thus if results are needed urgently, the lab personnel must be contacted, by a senior member of our team, to arrange earlier transport. PAEDIATRIC SPECIMEN BOTTLES USED ON NICU Lithium heparin: green top Fluoride oxalate: yellow top EDTA: lilac top Substance Sample Special measures PLEASE adhere to these Ammonia 500 micro litres Immediately put bottle in ice EDTA Transport to lab immediately Lab where processed Morriston Lactate Plasma amino acids Carnitines Free fatty acids VLCFA Ketones (3-hydroxy butyric acid) Insulin & C-peptide 500 micro litres Fluoride oxalate 600 micro litres Lithium heparin 3 X blood spots on Guthrie card 500 micro litres Fluoride oxalate 600 micro litres Lithium heparin 500 micro litres Fluoride oxalate 600 micro litres Lithium heparin Send to lab immediately Send to lab immediately Immediately put bottle in ice Transport to lab immediately Singleton UHW, Cardiff UHW, Cardiff UHW, Cardiff Southmead Hospital, Bristol UHW, Cardiff UHW, Cardiff ACTH 500 micro litres EDTA Immediately put bottle in ice Transport to lab immediately Cortisol 600 micro litres Lithium heparin Growth hormone 600 micro litres Lithium heparin Remember diurnal variation not well developed in neonates UHW, Cardiff Morriston Morriston 22