3. IEM --------- disease burden
Individually rare but the cumulative more common
3-4 /1000 live births
20% of acute illnesses in newborns (developed countries)
5% of mental retardation are due to IEM
Varied presentations
Few potentially treatable causes
Counselling for future risk/ antenatal diagnosis
5. Intermediary metabolism and IEM
• Intermediary metabolism ------ provides cells with vital energy and building
blocks
Catabolism. Anabolism
IEMs ------ disrupt the flow of energy and substrates between cytosolic macromolecules
and their catabolic end products
6. Various Metabolic Pathways in health
Any disruption in the flow of above pathways ------- metabolic decompensation
7. Pathophysiology of IEM ------ various mechanisms
• Deficiency of critical energy
substrates
• Accumulation of intoxicating
metabolites
• Production of endogenous
cytotoxins
Therapy of metabolic crisis ------- exogenous replacement of energy coupled to rapid
reduction of cytotoxins
8. Pathophysiology ------ various mechanisms
Intoxication Energy deficient Complex molecule
S/s due to accumulation of toxic compounds
proximal to metabolic block
due deficiency in energy
production or utilization in
liver, muscles, brian,
myocardium
Disorders that disturb the
synthesis or catabolism of
complex molecules
Cellular organelles
Features Initial symptom free interval
Acute- vomiting,coma, respiratory
abnormalities, hiccups, apnea,
bradycardia,liver failure, hypotonia
Chronic- dev delay, FTT,
cardiomyopathy.
• Hypoglycemia,
• hyperlactatemia
• hepatomegaly
• severe generalised
hypotonia
• FTT
• sudden deaths in
infancy
Permanent and
progressive S/S
Independent of
intercurrent events
No relation to food intake
Examples •Aminoacidopathies
•Organic acidemias
•Urea cycle disorders,
•Sugar intolerances
(Galactosemia,Fructosemia)
•Mitochondrial disorders
•Cytoplasmic energy
defects (glycolysis,
glycogen metabolism
disorders,
gluconeogenesis,
Hyperinsulinism)
•Peroxisomal disorders,
•NKH, Molybdenum
cofactor deficiency
Primary lactic acidosis
LSDs, Peroxisomal
disorders, disorders of
intracellular trafficking
(CDGs), cholesterol
metabolism.
9. Biological stress response
Autonomic and endocrine actions
degrade tissue glycogen, fat and
protein to supply vital organs with
glucose and beta- hydroxybutyrate
Metabolic crisis --------- failure of stress adaptation
10. IEM ------ acute metabolic crisis to ER
• Acute decompensation after a period of apparent well being ----- metabolic
crisis
• Presents to ER as acute emergency ------ morbidity / progresssive neurological
injury / death
• Optimal outcomes ----- requires recognition and prompt evaluation &
management
increased catabolism ---- acute infection, surgery
• Triggers trauma, fasting
increased consumption of food component
11. Metabolic crises ------ suspicion is ER is utmost important
• Protean manifestations
85% -------- neurological symptoms / signs
51% ------- GI symptoms
12. Metabolic crises ------ Clinical presentation
• Present with non specific manifestations ---- poor feeding, lethargy, vomiting,
hypotonia , seizures, failure to thrive
• Rapid deterioration of general condition or reduced consciousness
• Rapidly progressive encephalopathy of unknown etiology
• Family history of neonatal death or parental consanguinity
• Unexplained metabolic acidosis, peculiar odour
13. IEM --------- disease burden
• Out of 175, 66 (38.5%) children had
IEMs
• The median age of diagnosis was 12
months
• M: F ratio was 2.4:1
• Out of these, 27(42%) had a positive
history of death of siblings with
similar problem
• Consanguinity was reported in 11/28
(17.5%) of the affected families
Organic acidemia
54%
Methyl malonic
acidemia
Aminoacidopathie
s
16%
MSUD-
Mitochondrial
14%
Fatty acid
oxidation defect
11%
Urea cycle defect
6%
Types of IEM
20. Approach to Hypoglycemia in IEM
• Ketonuria in newborn ----
organic acidemia or
mitochondriopathy
• In infancy B-hydroxybutyrate
is predominant ketone
• Urine – clinistix test detects
only acetone and acetoacetate
• Important in evaluation of
hypoglycaemia- hypoketosis
in FAOD and
hyperinsulinemia
21. Approach to blood lactate and pyruvate in IEM
Lactate and Pyruvate are normal metabolites
• Pyruvate - Only helpful in primary lactic acidosis
• Lactate/pyruvate ratio- normal is 20:1
• Decreased (<10) - PDH deficiency
• Increased (>25) -tissue hypoxia, pyruvate carboxylase deficiency,ETC abnormalities
Blood lactate <2.1mmol/L (<19mg/dl)
CSF lactate <1.8 mmol/L (16mg/dl)
22. Other investigations in IEM -------- TMS and GCMS
Acylcarnitine elevated- organic
acidemias and FAOD
Analysis requires only minutes
Allow rapid preliminary diagnosis
organic acidemia and FAOD
TMS cannot distinguish between
two acylcarnitines with same
molecular mass
Urine ------ preferred sample for
organic aciduria screening
24. Laboratory investigations ------ 5 simple tests in ER
Group Acidosis Ketosis Plasma Lactate Plasma NH3 Plasma
Glucose
Diagnosis
I ± ++ N N N/↓ Maple syrup urine
disease
II +++ + N/↑ ↑↑ ↓↓/n/↑ Organic acidurias
III ++ ± ↑↑↑ N N Mitochondrial electron
transport
Chain defects
IV N N N ↑↑↑ N Urea cycle disorder
V ± N ± ↑ ↓↓↓ Fatty acid oxidation
defects, Hyperinsulinemia
25. Treatment ------- Evidence and Practice
• Most interventions for IEMs lack a strong evidence base and instead are based
on a combination of physiological reasoning, expert opinion and individual
experience
• Prespecified protocols ----- useful starting point
• Categorizing an IEM into several discrete clinical paradigms helps to clarify
treatment priorities
27. Metabolic crisis management ----- GOALS
• Prevention of further accumulation of harmful substances
• Correction of metabolic abnormalities
• Elimination of toxic metabolites
28. Metabolic crisis management ------ treatment protocol
A. Immediate elimination of dietary or parenteral intake of potentially toxic
compounds --------- Protein, fat, galactose and fructose
B. Prevent catabolism
• Administer high calorie, high carbohydrate IV fluids ----- 10%D in NS at 1.5
times maintenance
• Start atleast 60Kcal/kg/d and can be increased upto 120kcal/kg/d
NPO -------- usually for 24-48hours until crisis resolve
29. Metabolic crisis management ------ treatment protocol
• Withhold intake of protein
For about 48hours and not for indefinite period
Essential aminoacids ----- orally or intravenously at an initial dose of
0.5g/kg/d 1g/kg/d
• IV intralipids may be used (provided FAOD has ruled out)
• Avoid Ringer’s lactate
30. Metabolic crisis management ------ Hyperammonemia
• Acute hyperammonemia ------ acute life threatening condition that can lead
to severe neurological impairment and cerebral edema
• UCDs ------ 23% of acute hyperammonemia in critically ill children
• Other ----- organic acidurias, mitochondrial disorders
33. Metabolic crisis management ------ correct metabolic acidosis
• Metabolic acidosis ------ treated cautiously
Q1: Should bicarbonate infusion used in severe metabolic acidosis?
if pH<7.2 or bicarbonate <10mmol/L
Q2: In what situations RRT should be used?
• Severely acidotic infants pH <7.1 , despite appropriate treatment
34. Metabolic crisis management ------ correct hypoglycemia
• Use 10%D glucose -------- 8 to 12 mg/kg/min at 1-1.5 times maintenance
• Maintain serum glucose level ----- 120 to 170 mg/dl
• Any child in metabolic crisis ------ dextrose
is infused to meet or exceed endogenous
glucose production rate (EGPR)
• Dextrose 10% at maintenance rate
approximates EGPR in children >5years of
age, but higher rates are required for
younger children
• Dextrose 25% via central venous line meets
/exceeds EGPR at submaintenance infusion
rates, minimizing complications of
hypervolemia
35. Metabolic crisis management ------ Role of Insulin
• Insulin ------ antagonize the actions of several counterregulatory hormones
and is thus a powerful ally in the reversal of catabolic states
• Its anabolic effects are especially useful for reducing the generation of protein
derived toxins such as leucine and ammonia
• In MSUD and UCDs ----- continuous insulin recommended
Insulin is contraindicated ------ GSD and FAOD
Dosage: 0.02 – 0.15 units/kg/hour
(Blood glucose concentration titrated to 100-160mg/dl)
36. Metabolic crisis management ------ L-Carnitine therapy
• Intravenous L- carnitine clears cytotoxic acyl-CoA thioesters from the
mitochondrial matrix and increases cellular availability of unconjugated CoA
• Recommendation ------ In organic acidemias in metabolic crisis
50-100 mg/kg/dose every 6-8 hours
The metabolic response ------ quantified by urinary excretion of acylcarnitine
conjugates
38. Role of Hemodialysis
Severe hyperammonemia (>350)
• Target blood flow ----
150ml/m2 through the largest
catheter
• HD clears ammonia 10 times
faster than PD /
hemofiltration
• Exchange transfusion is
ineffective
Children in IEM crisis ----- usually have cerebral edema
Dialysis parameters should be carefully designed to prevent any hypotonic changes of
Serum Osmolality
• MSUD
• Short courses of HD
accelerate the clearance of
toxic metabolites
39. Metabolic crisis management
Finally,
PICU follow up:
Confirm the primary diagnosis ----- to collect the work up
To assess any sequalae
To educate about the precipitating triggers and prevent decompensation
Diet counselling and ensure specific therapy
Genetic counselling
