Post on 15-Dec-2015
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Inborn errors of metabolism:
emergency management
Classification of inborn errors of metabolism: (IEM)• I: Intoxication disorders
• II: energy metabolism disorders
• III: complex molecules disorders
Presenting features
Acute presentation• Vomiting• Dehydration• Lethargy• Coma• Rhabdomyolysis• Heart failure• Liver failure • ALTE• Respiratory failure (as complication)
Chronic presentation • FTT• Hepatomegaly• Cardiomyopathy• Developmental delay• Developmental regression
Triggers for decompensation
Increased catabolism Increased consumption
• Fasting• Surgery• Trauma• infection
• Increased protein consumption
Metabolic Causes of acute decompensation
Neurology---------------
MSUDMMAPAIVAMCDUCDFAORCD
SEIZURE--------------
B6 responsiveMCDFolonic acid disordersGlucose up-take
Liver failure-----------------
GALACTOSEMIATyrosinemiaBile acid synthesisRCDGSD
Cardiac failure &Cardiac beat, ALTE---------------
Carnitine disordersFAOStorage diseases
Neurology decompensation(acute encephalopathy)Definitions:
• Consciousness: a state of general wakefulness and responsiveness to environment
• Coma: A state of deep, unarousable, in which the person shows no meaningful response to environment
consciousness sleep lethargy stupor coma
Background physiology
Consciousness requires two components:
1- Arousal or wakefulness, dependent on the function of Reticular Activating System (RAS), a network of neurons located in the brainstem extending from pons to thalamus
2- Awareness, mediated through cerebral neurons
• Awareness requires wakefulness and not vice versa
structural Metabolic-toxictrauma Hypoxia-ischemia
neoplasm Metabolic disordersHypoglycemia, hepatic,
electrolytes, DKA, uremiaVascular
Infarction, haemorrhage, vasculitis
infection
Focal infectionAbscess, cerebritis
Paroxysmal disordersEpilepsy, migraine
hydrocephalus
Classification of causes of acute encephalopathy
Patient assessment
• Primary survey:
A B C DISABILITY – Glascow Coma Scale , useful objective tool for the quantification of the consciousness-coma continuum
• Secondary survey:
Glascoma scoreEyes open spontaneously +4
Eye opening to verbal command +3
Eye opening to pain +2
Eye opening to pain +1
Not assessable 0
Best Verbal Response
Oriented +5Confused +4Inappropriate words +3Incomprehensible sounds +2No verbal response +1Intubated 0Best Motor Response
Obeys commands +6Localizes pain +5Withdrawal from pain +4Flexion to pain +3Extension to pain +2No motor response +1
Investigations of encephalopathy patient
Laboratory investigations• CBC• Electrolytes• LFT• Coagulation profiles• BUN, Cr, Ca, Mg, PO4• Ammonia• Lactate• CPK• Glucose• ABG
Imaging studies• CT/MRI• MRI
HYPOGLYCEMIA
acidemia No acidemia
LA KETONESI
G6PDF1,6P
NormalKetotic hypoglycemiaDebrancher enzymeGH dCortisol d
I FFA
ketones
FAO
FFA
ketones
hyperinsulinism
HYPERAMONEMIA
Bedside differential diagnosis of inborn errors of metabolism presenting with hyperammonemiaParameter Condition
UCDs Organic acidurias
β-Oxidation defects
Hyperinsulinism-
hyperammonemia
syndrome
Pyruvate carboxylase deficiencyg
Acidosis +/– + e +/– – +Ketonuriaa – + – – ++Hypoglycemiab – +/– + + +
↑ Lactic acidc – + +/– – +↑ AST & ALT (+)d – + – +/–↑ CPK – – + – –↑ Uric acid – + + – –↓ WBC/RBC/Plt – + – – –
Weight loss – +f – – +
In addition to the conditions indicated in the table, mitochondrial oxidative phosphorylation defects, citrin deficiency, lysinuric protein intolerance or
findings MSUD OA UCD DCM FAO MD PD LSDMetabolic acidosis
+-
++ - +-
+-
+-
- -
Respiratory alkalosis
- - + - - - - -
Hyperammonemia
+-
+ +++ - +-
+-
- -
Hypoglycemia +-
+-
- + - +-
- -
Ketones A/H H A A/H A/L A/H A ALactic acidosis =
-+-
- + +-
++ - -
DISTINGUISHING BIOCHEMICAL FINDINGS OF IEM
Emergency treatment
• Ventilator support• Fluid resuscitation with saline• Hypoglycemia: 7-10 mg/kg/min, keep blood sugar more than 5.5mmol/l• Hyperammonemia: glucose 10mg/kg/min over 2 hours: Arginine 360mg/kg Na benzoate & or phenylacetate 250mg/kg (max 500/kg) carnitine 100mg/kg maintains: as above Carbaglu in organic academia and UCD 100-200/kg stat, then 100 mg/kg/d
• Metabolic acidosis: PH (more than 7.3) 4-6 meq/kg/d PH (less than 7.3) 1-2 meq/kg/hr to be tapered accordingly
DisorderDistinctive Features
Ketosis Acidosis Other cofactor
Maple syrup urine disease (MSUD) 1
X Maple syrup odor thiamine
Propionic academia 2 X X Neutropenia biotin
Methylmalonic acidemia (MMA) X X Neutropenia B12
Methylmalonic aciduria and homocystinuria, cblC type
Rare RareVomiting, poor feeding, neurologic symptoms
B12, pyrodoxin
Isovaleric academia 1 X Sweaty feet odor
Biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency
X Hypoglycemia
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency
Reye syndrome, hypoglycemia
Ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase deficiency)
X X Hypoglycemia
Glutaricacidemia type I (GA I)
Basal ganglia injury with movement disorder
riboflavin
Clinical Findings in Organic Academia's Caused by Abnormal Amino Acid Catabolism
Acute management of newborn with suspected organic acidemia1) The patient is kept nil per orally and intravenous glucose is provided.2) Supportive care: hydration, treatment of sepsis, seizures, ventilation.3) Carnitine: 100 mg/kg/day IV or oral.4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)5) Start Biotin 10 mg/day orally.6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms ofmethylmalonic acidemias)7) Start Thiamine 300 mg/day (useful in thiamine-responsive variants of MSUD).8) If hyperammonemia is present, treat as explained above.
Discontinue all feeds. Provide adequate calories by intravenous glucose andlipids. Maintain glucose infusion rate 8-10 mg/kg/min. Start intravenous lipid 0.5g/kg/day (up to 3g/kg/day). After stabilization gradually add protein 0.25 g/kg till1.5 g/kg/day.2) Dialysis is the only means for rapid removal of ammonia, and hemodialysis ismore effective and faster than peritoneal dialysis, however peritoneal dialysis maybe more widely available and feasible. Exchange transfusion is not useful.3) Alternative pathways for nitrogen excretion-:Sodium benzoate (IV or oral)- loading dose 250 mg/kg then 250-400 mg/kg/dayin 4 divided doses. (Intravenous preparation not available in India).Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followedby 250-500 mg/kg/day.L-arginine (oral or IV)- 300 mg/kg/day (Intravenous preparation not available inIndia)L-carnitine (oral or IV)- 200 mg/kg/day4) Supportive care: treatment of sepsis, seizures, ventilation. Avoid sodiumvalproate.
Treatment of hyperammonemia
Supportive care: hydration, treatment of sepsis, seizures, ventilation. Avoidsodium valproate.2) Treat acidosis: sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr)3) Thiamine: up to 300 mg/day in 4 divided doses. Riboflavin: 100 mg/day in 4 divided doses.5) Add co-enzyme Q: 5-15 mg/kg/day6) L-carnitine: 50-100 mg/kg orally.7) Biotin 10 mg/day. (Biotin responsive Multiple carboxylase deficiency maypresent with unexplained lactic acidosis)12