ESPEN Congress Madrid 2018

Transcription

1 ESPEN Congress Madrid 2018 Inborn Errors Of Metabolism Urea Cycle Disorders Diagnosis And Care F. Feillet (FR)

2 Urea cycle disorders, diagnosis and care F Feillet National reference centre for Inborn errors of Metabolism, Nancy, France

3 F Feillet: disclosures Scientific boards: Biomarin, Genzyme, Shire, Merck-Serono, Nutricia Congress invitations: Biomarin, Genzyme, Merck-Serono, Nutricia, Vitaflo, Alexion Honoraria: Biomarin, Genzyme, Merck-Serono, Nutricia, Alexion, Vitaflo

4 et al

5 UCD stories Male neonate Normal birth 2 nd day: vomiting Hiccup, drowsiness Status epilepticus, coma and death Biology: Alkalosis Hyperammonemia Diagnostic: Severe OTC deficiency Young lady, 23 years old She married a boy who loves eating meat Chronic nausea, stunting Hospitalized for anorexia nervosa Biology Mild hyperammonemia Diagnostic: Mild OTC deficiency

6 Nutrition of macronutrients CARBOHYDRATES PROTEINES LIPIDS Gluose Glycogene Fatty acids Anabolism AMINOACIDS Catabolism

7 Nutrition of macronutrients CARBOHYDRATES PROTEINES LIPIDS Gluose Glycogene Fatty acids Anabolism AMINOACIDS Catabolism

8 The protein metabolism Alimentary proteins Endogenous proteins Proteins degradation Proteins synthesis 75-80% Amino acids Catabolism % Neoglucogenesis Nitrogen compounds synthesis

9 Amino acids metabolism COOH - R - NH 2 Glycine 2 x COOH - CH 2 - NH 2 Glycine 2 x COOH - CH 2 - NH 2 2 x (CO2 + NH 3 + MTHF) 2 x (CO2 + NH 3 + MTHF) Urea NH 2 - CO - NH 2 Urea NH 2 - CO - NH 2 NH 3 Urines

10 Glutamate Acetyl-CoA Citrulline Glutamine 3 N-acetyl glutamate NH 3 Carbamoyl phosphate 1 2 Catabolism of AA 1 : Ornithine transcarbamylase 2 : Carbamoyl phosphate synthetase 3 : N-acetyl glutamate synthetase 4 : Argininosuccinate synthetase 5 : Argininosuccinate lyase 6 : Arginase 7: ORN-CIT transporter (triple H Sd) Ornithine Mitochondria orotic acid (urines) Aspartate Citrulline 7 4 Argininosuccinate 5 Fumarate 7 6 Arginine Ornithine Urea Cytosol Urines

11 Ureogenesis in OTC deficiency Normal Girl Sick boy Yudkoff J Clin Invest 1996, 98;

12 Diagnosis

13 Risk factors of metabolic decompensation Excessive protein intake Surgery Starvation Excessive physical activity Intercurrent disease

14 UCD: clinical symptoms Neonatal (acute) onset Vomiting and progressive poor appetite Temperature instability lethargy to coma Seizures Multiorgan failure Peripheral circulatory failure Sepsis-like picture Respiratory distress Hyperventilation (alkalosis) Late (chronic) onset Protein aversion, self-selected low-protein diet Failure to thrive Confusion, lethargy, dizziness Migraine-like headaches, tremor, ataxia, dysarthria Abdominal pain, vomiting Hepatomegaly, elevated liver enzymes Psychiatric symptoms: hyperactivity, mood alteration, behavioral changes, aggressiveness

15 Pedigree analysis Neonatal deaths Meat aversion, mild symptoms OTC deficiency

16 Diagnostic: hyperammonemia UCD Diagnosis Blood ammonia Plasma Amino acids Urinary orotic acid Differential diagnosis Urinary organic acids Carbamylglutamate loading test Lactate pyruvate ratio Plasma acylcarnitines

17 Diagnosis of hyperammonemia Symptomatology before 24 hours Yes Premature At term No IEM HAN IEM Acidosis and/or ketosis Gln PDH Yes No: GA II PA, MMA UCD Others Others Citrulline Low mmol/l >1000 mmol/l U Orotic acid Plasma ASA - + CPS OTC ALD ASD Carbamylglutamate loading test + : NAGS

18 Differential diagnosis of metabolic causes of hyperammonemia

19 Management

20 Main goals of acute UCD management It is a major emergency +++ (transfer in ICU +++) Hours (not days) of delay can severely impair the prognosis!!! Sample the metabolic parameter Stop protein intake Prescribe nitrogen scavengers Prepare Hemofiltration if needed: Neurological signs NH3> 500 µmol/l)

21 Main goals of acute UCD management It is a major emergency +++ (transfer in ICU +++) Hours (not days) of delay can severely impair the prognosis!!! Sample the metabolic parameter Stop protein intake Prescribe nitrogen scavengers Prepare Hemofiltration if needed: Neurological signs NH3> 500 µmol/l)

22 Management of acute hyperammonemia It depends of the level of plasma ammonia! Sample all biological parameters in emergency STOP protein intake Induce anabolism Ammonia withdrawal Restore the metabolic pathway (NAGS deficiency) High caloric intake Carbohydrates, lipids and vitamins Drugs Phenylbutyrate Benzoate Carbamylglutamate loading test (p.o) Extracorporeal detoxification: Hemofiltration

23 Management of hyperammonemia in UCD

24 Main goals of chronic UCD management To reach the normal protein requirements for age +++) Nitrogen, essential amino acids To obtain a good metabolic control (Normal ammonia, normal glutamine: < µmol/l) To avoid the metabolic decompensation To obtain a normal growth (! Energy intake) To obtain a normal psychomotor development

25 Bad metabolic control Input Alimentary nitrogen Drug nitrogen Catabolism > NH3 Output Urea Extrarenal Nitrogen loss (20 %) Nitrogen scavengers (drugs) Growth, anabolism

26 Good metabolic control Aim: to avoid Nitrogen (ammonia) accumulation Input Alimentary nitrogen Drug nitrogen Catabolism Output Urea Extrarenal Nitrogen loss (20 %) Nitrogen scavengers (drugs) Growth, anabolism

27 UCD: a three steps diet Complete micronutrient status Optimize energy requirements Minimum protein intake (+/- amino acids supplementation)

28 Protein requirements

29 Protein content of different foods Food Meat Milk Green beans Carots Cabbage Rice Apple / 100g 970 mg 170 mg 73 mg 31 mg 140 mg 390 mg 9 mg 2g of meat = 215 g of apple

30 +Essential AA if needed NO Yes Low protein diet Controled quantity

31 Energy supplements Glucido-lipidic supplements Low-protein foods Without miconutrients Super Soluble Duocal Super Soluble Maxijul With miconutrients Energivit PFD1 PFD2 Pause dessert

32 Low-protein foods

33 Nitrogen scavengers Benzoate and phenylbutyrate N!! Excretion of Benzoyl carnitine Urines 2 Nitrogen 1 Nitrogen Activation of BCKAD Decrease Leu, Ile and Val N N

34 Drugs dosages in UCD

35 Glycine Encephalopathy. Van Hove J, Coughlin C II, Scharer G GeneReviews 2002 Nov 14 [updated 2013 Jul 11]

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37 Isoleucine deficiency

38 Essential or specific amino acid deficiency Supplémentation spécifique - Isoleucine - Valine - Leucine - Phénylalanine -

39 Arginine becomes an essential AA In CPS, OTC - Give Citrulline (3N) + Aspartate

40 Arginine becomes an essential AA In ASS, ASL - Give arginine (4N)

41 One specific treatment for NAGS deficiency Acetylglutamate Carbamylglutamate

42 Amino acids levels in an OTC girl

43 Compliance difficulties! Adherence issues in inherited metabolic disorders treated by low natural protein diets. MaCdonald A 1, van Rijn M, Feillet F, et al Ann Nutr Metab. 2012;61(4):

44 Outcome of UCD Clinical course of 63 patients with neonatal onset urea cycle disorders in the years

45 et al

46 Thank you for your attention