Suspected Metabolic Disease in the Newborn Period Acute Management "What do I do?" Barbara Marriage, PhD RD Abbott Nutrition

Suspected Metabolic Disease in the Newborn Period Acute Management "What do I do?" Barbara Marriage, PhD RD Abbott Nutrition

Introduction Review clinical findings that may be suspicious of a metabolic disorder Review laboratories studies performed for suspected metabolic disorders Outline treatment guidelines Focusing on stabilization and acute management

Clinical Presentation Full term baby born after normal pregnancy and delivery Initially symptom-free Deteriorates for no apparent reason No response to symptomatic treatment

Why Are Metabolic Disorders Difficult to Diagnose Initially? Over 100 metabolic disorders can present in newborn period Individually rare - collectively enormous Lack of exposure during medical training - under diagnosed and/or delayed diagnosis Unknown number of infants with metabolic disorders die prior to diagnosis and treatment!

Clinical Clues in the Newborn Overwhelming illness in the newborn period Non-specific symptoms Vomiting/diarrhea Poor sucking reflex Lethargy Failure to thrive Seizures/cerebral edema Unusual odor Abnormal muscle tone Family history of siblings dying young

Metabolic Disorders Presenting in the Newborn Urea cycle disorders Organic acidemias Maple syrup urine disease (MSUD) Galactosemia and Glycogen Storage Disease Tyrosinemia Fatty acid oxidation disorders Nonketotic hyperglycinemia Pyruvate dehyrogenase deficiency Pyruvate carboxylase deficiency

Laboratory Studies for Suspected Metabolic Disorders CBC with differential Urinalysis Blood gases Urine reducing substances Serum electrolytes Blood glucose Plasma ammonia Plasma lactate Urine ketones if acidosis or hypoglycemia present Urine organic acids and amino acids Plasma amino acids

Detection of Metabolic Disorders Newborn Screening Expanded newborn screening - Tandem MS Special Diagnostic Studies Quantitative urine organic acids Urine acylglycines/acylcarnitines Plasma carnitine/acylcarnitine profile Lactate/pyruvate ratio Enzyme analysis Genetic mutation analysis

Metabolic Encephalopathy Clinical Signs Lethargy, poor feeding, recurrent vomiting, respiratory distress, hypotonia, abnormal movements Laboratory Signs Hyperammonemia, acidosis, ketosis Possible Diagnosis Urea cycle defects, MSUD, organic acidemias (MMA, PA, IVA), glutaric aciduria type I

Hyperammonemia Urea cycle disorders (> 600 µmol/l) Organic acidemias Fatty acid oxidation defects (moderate elevation) Onset with protein ingestion or significant catabolism THAN (transient hyperammonemia of the newborn) Usually large premature infants (> 30 weeks) with symptomatic pulmonary distress Liver dysfunction, sepsis, herpes simplex, asphyxia (moderate elevations)

Metabolic Acidosis Organic acidemias MMA, PA, MCD, MSUD, IVA, GA I, GA II Laboratory Values Anion gap > 16 Normal anion gap with acidosis Diarrhea Renal tubular acidosis

Metabolic Acidosis Lactate Elevated lactate, Secondary to defective CoA metabolism Lactate/pyruvate ratio < 25 - Pyruvate dehydrogenase deficiency Defect in gluconeogenesis > 25 - Pyruvate carboxylase deficiency Respiratory chain disorders

Hypoglycemia Carbohydrate defects Glycogen storage disease (GSD1) Hereditary fructose intolerance Galactosemia (GALT) Fatty acid oxidation defects Non-ketotic hypoglycemia Family history of SIDS

Hypoglycemia Amino acid disorders May occur alone or with other biochemical rearrangements ± Ketoacidosis ± Lactic acidosis ± Liver failure, hepatomegaly

Liver Dysfunction Jaundice, hepatomegaly, elevated LFT's Galactosemia Urine reducing substances RBC galactose-1 phosphate uridyl transferase Hereditary fructose intolerance Deficient clotting factors

Liver Dysfunction Tyrosinemia Plasma amino acids, urine succinylacetone α1-antitrypsin deficiency Serum α1 antitrypsin, protease inhibitor typing Zellweger syndrome Plasma VLCFA

Other Presentations of Life-Threatening Metabolic Diseases Non-ketotic hyperglycinemia Severe CNS dysfunction No acidosis or increased NH 3 Molybdenum cofactor deficiency Indistinguishable from hypoxic-ischemic encephalopathy Galactosemia E. coli sepsis, jaundice, vomiting, increased intracranial pressure Importance of Laboratory Assessment

Abnormal Odor and Dysmorphic Features Odor MSUD (maple syrup or burnt sugar) Isovaleric acidemia and GA II (sweaty feet) Eye Findings Cataracts Galactosemia, Zellweger, Lowe syndrome Dislocated lens Homocystinuria, molybdenum cofactor deficiency, sulfite oxidase deficiency

Abnormal Odor and Dysmorphic Features Dysmorphic Features Zellweger Hypotonia, epicanthal folds, renal cysts, large fontanel GA II High forehead, hypertelorism, low-set ears, hypospadias PDH Similar to fetal alcohol syndrome Smith-Lemli-Optiz Cleft palate, hypospadias

Acute Nutrition Intervention Hyperammonemia (Urea Cycle Disorders) Adequate energy (100-130 kcal/kg/day) and fluid intake to prevent catabolism Provide alternate nitrogen pathway Sodium benzoate/phenylbutyrate (500 mg/kg/day) L-Arginine (except in Arginase deficiency) (300-600 mg/kg/day) Dialysis/exchange transfusion

Acute Nutrition Intervention Hyperammonemia (Urea Cycle Disorders) Remove all protein sources until hyperammonemia resolved Parenteral IV glucose + lipid Enteral Pro-Phree May need a combination of both Slowly start protein (0.5 to 1.5 g/kg) Parenteral Amino acid solution Enteral Cyclinex-1

Acute Nutrition Intervention Organic Acidemias (Metabolic Acidosis) Adequate energy (100-130 kcal/kg/day) and fluid intake to prevent catabolism Reduce protein (0.5-1.5 g/kg/day) Add Pro-Phree to infant formula Use of Propimex etc, if disorder identified Carnitine supplementation AVOID FASTING!

Clinical Manifestations of FAO Disorders Fasting intolerance Hypoketotic hypoglycemia Liver dysfunction and hepatomegaly Sudden or unexpected death Family history of SIDS Asymptomatic

What Happens When We Fast? Glycogen Protein Fat Amino Acids Fatty Acids Glucose Ketones

What Happens in FOD? Fatty Acids Ketones Lack of Energy Growth development Cardiomyopathy Arrhythmia Muscle pain tone Sleepy consciousness

Clinical Manifestations of FAO Disorders Cardiomyopathy Rhabdomyolsis, muscle pain AFLP (acute fatty liver of pregnancy) HELLP syndrome (hypertension, elevated liver enzymes, low platelets)

Clinical Presentation of MCAD MCAD ~ 1 in 10,000 births Triggered by fasting and/or intercurrent illness Vomiting, lethargy, hypoketotic hypoglycemia Acute liver disease NH3, LFT, ± acidosis Mortality rate before diagnosis ~ 20% Prognosis excellent once diagnosis established

Acute Nutrition Intervention Fatty Acid Oxidation Defects Reduce fat MCAD 25-30% of energy (controversial) Long Chain - FAOD 20-30% of energy (15% as MCT) Use of ProViMin, Glucose polymers, Portagen, Monogen, Lipistart MCT, vegetable oil

Acute Nutrition Intervention Fatty Acid Oxidation Defects Assure adequate essential fatty acids Adequate protein, energy, and fluids Carnitine supplementation AVOID FASTING!

Acute Nutrition Intervention Hypoglycemia Acute glucose infusion (5-7 mg/kg/min) With cardiac failure 10-12 mg glucose/kg/min (may need insulin to prevent lipolysis) L-carnitine With liver dysfunction Remove galactose in galactosemia Remove fructose in HFI Remove protein in tyrosinemia

Nutrition Intervention Disorder Galactosemia Hereditary fructose intolerance Glycogen storage disease PDH deficiency, GLUT 1 deficiency Intervention Remove galactose Remove fructose, sucrose Prevent fasting Limit galactose/ fructose High fat/ low carbohydrate To Meet Nutrition Needs Soy-based formula Breast milk, milk-based formula RCF, soy based formulas, added glucose RCF + lipid

Additional Nutritional Therapies Therapy Insulin L-Carnitine Biotin B-12 Riboflavin Thiamin Dosage 0.2-0.3 IU/kg/h 50-100 mg/day 10 mg 1-2 mg/day 20-40 mg/day 10-50 mg/day Disorder Severe catabolism Organic acidemias, Fatty acid oxidation defects Multiple carboxylase deficiency Methylmalonic acidemia Glutaric aciduria MSUD, hyperlactacidemia

Principles of Emergency Management Stop intake of all potentially toxic compounds Protein, fat, galactose, and fructose Promote anabolism This is a vital step Protein-free calories for the 1 st 24-48 hours Correct acid-base status Anion gap = ([Na + ]) ([Cl - + [HCO 3- ]) Normal AG = 12 + 2 meq/l (acidotic = >16 meq/l) Correct and maintain blood glucose Initiate procedures to remove toxins Extracorporeal toxin removal Conjugating agents

Indications for Parenteral Nutrition Comatose Acute illness with hyperemesis or intolerance to enteral feeds Severe metabolic decompensation For planned surgeries and deliverie Intractable diarrhea Patient cannot consume sufficient energy to meet energy and/or protein needs " IF THE GUT WORKS, USE IT! "

Types of Parenteral Nutrition Therapy Peripheral Through a peripheral vein Osmolality < 900 mosm/kg Difficult to provide adequate calories/nutrition Central Requires central vein access Osmolality > 900 mosm/kg

TPN in the Management of IEMs Requirements will depend on degree of metabolic decompensation Promote anabolism & stop catabolism High calorie & often protein free Will need protein source ( >48 hours) or will become catabolic Combination of enteral + parenteral Benefits of trophic feeds Enhance feeding tolerance

Nutrition Management of Hypometabolism Total Parenteral Nutrition (TPN) (may need to adjust CHO, fat, protein) TPN + Enteral Feeding Enteral Feeding + IV Glucose Full Enteral Feeding

TPN in the Management of IEMs Energy requirements during metabolic decompensation REE increased by 30-40% during metabolic decompensation Bodamer et al. Eur J. Pediatr. 1997; 156(1):24-28. Adjust/compensate for the PO intake In disorders of energy metabolism (pyruvate dehydrogenase complex deficiency) glucose is contraindicated 2-4 mg/kg/min glucose

TPN in the Management of IEMs In FAODs, severe energy deficit is noted 10-12 mg/kg/min glucose to suppress lipolysis Select appropriate calorie source if suspicious of FAODs 15-30% Polycose or glucose polymers for MCAD Van hove et al. Mol Genet Metab. 2009; 97:1-3.

TPN in the Management of IEMs Glucose at appropriate rates + introduction of EAAs within the 48-72 hour window is critical TPN - protein free initially (first 48 hours) but need protein (EAAs) to prevent catabolism by 72 hours Can use available commercial AA solutions Initially provide minimum requirements Based on what was prescribed and tolerated at home Monitor to determine trend and adjust AA should be provided over 24 hours and not cycled Specialized AA free solutions are available but are very expensive

TPN in the Management of IEMs May need to modify with single AA solutions per levels Supplemental amino acids - isoleucine and valine may become rate limiting for protein synthesis in MSUD In UCDs, supplementation with BCAAs when phenylbutyrate is used has been proposed Help with improved control and decreased likelihood of catabolism Scaglia et al. Mol Genet Metab. 2004; 81:S79-S85.

Management of Suspected Metabolic Disorders If diagnosis is suspected - start emergency management DO NOT ALLOW FASTING! Ventilatory and circulatory support for ill newborns Rehydration and correction of electrolytes Concomitant sepsis (organic acidemias are at increased risk)

Management of Suspected Metabolic Disorders Nutrition is pivotal! Restrict protein diet - UCD, organic acidemias Normal diet - higher glucose Restricted fat diet FAOD s Restricted carbohydrate diet - PDH Do not over treat without specific diagnosis

Questions March 2014 Saudi Arabia