Download Metabolic emergency

MANAGEMENT OF
METABOLIC
EMERGENCIES
By
Prof. MANAL ELDEFRAWY
Awareness of some IEM 2011
Objectives
 When to suspect a metabolic
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disorder?
Immediate investigations
Specific investigations
Which emergency measures?
Diagnostic algorithm
Case presentation
 Single gene defect in an enzyme or transport
protein, which results in a block in a metabolic
pathway of proteins ,CHO, fats, or complex
molecules.
 Effects are due to:
toxic accumulations of substrates before the
block, intermediates from alternative
metabolic pathways, defects in energy
production caused by a deficiency of products
beyond the block,
or a combination of these metabolic deviations
The incidence, collectively, is
estimated to be approximately
1 in 4000 live births
The inheritance is mostly
autosomal recessive with male to
female ratio of 1:1
When To think Metabolic
Time & Pattern of Onset
Neonatal period
A) Intoxication type
Typically born healthy, symptom free period
Deterioration with poor feeding, vomiting, lethargy, apnea
seizures, coma.
e.g. a.acidopathies, Organic acidemia, UCDs , CHO intolerance.
B) Energy deficiencies
No apparent Symptom free
Overwhelming neurologic deterioration apnea, seizures, coma
e.g. FAO defects, Mitochondrial disorders, peroxisomal disorders
When To Think Metabolic?
Beyond neonatal period
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Lethargy or just not doing well
Refusal to feed poor suckling
Vomiting
Poor weight gain
Hepatomegaly
Tachypnea
Hypothermia
Axial hypotonia
Limb hypotonia
Abnormal movements(pedalling , tremors)
Altered conscious, seizures, coma
Multivisceral failure
When to think metabolic?
Additional factors
 Consanguinity
 Unexplained Neonatal deaths
 Unexplained Deterioration with
symptomatic treatment
Initial investigations
parallel to Sepsis screening
Urine
 Ketonuria bedside test
 Unusual Odour
 Unusual colour
 Reducing subtances
Blood
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Glucose
Electrolytes: Na,K,cl,Ca
Ammonia
Blood gases
Anion gap
 Transaminases
 Prothrombin T&C & INR
 Urea & creatinine
 Uric acid
 Lactic acid
 CK
 CBC
Second Line Evaluation
 Urine and plasma aminogram
 Urine organic acid profile by GC-MS
 Plasma carnitine and Acyl carnitine
profile:
Increase carnitine ester in fatty acid
oxidation defect, organic academias,
ketosis
 Dried blood spot analyzed by tandem
mass spectrometry (MS/MS).
Second Line Evaluation(cont.)
 CSF anaylsis
NKH is diagnosed by the presence of elevated CSF to
plasma glycine ratio
Decrease CSF glucose/to blood glucose…..glucose
transporter defect
 Peroxisomal function Test
Plasma very long chain fatty acids (VLCFAS),
Phytanic acid, erythrocyte plasmalogen levels
 Stored samples
Frozen whole and heparinized bl., serum, CSF
& urine (store at -20°C).
Emergent treatment of IEMs
(acute life-threatening )
 Establish airway, breathing, circulation.
 Avoid lactated Ringer’s.
 Avoid hypotonic fluid load due to the risk of
cerebral edema (if hyperammonemia is present).
 NPO :Discontinue intake of offending agents;
(especially no protein, galactose, or fructose)
 Provide adequate glucose to prevent catabolism.
(Fluid boluses D10 normal saline).
Most IEMs with acute life-threatening
presentation can be categorized based on
finding of at least 1 of the following :
 Hyperammonemia
 Metabolic acidosis
 Hypoglycemia
 Jaundice and Liver dysfunction
Hypoglycemia
Severe, persistent, without other etiology
If with metabolic acidosis e.g. OA,
GSD Type 1 , Fructose 1,6 Diphosphatase
deficiency, FAO (hallmark Non ketotic)
N.B :Hypoglycemia (plasma glucose level
< 50 mg/dL)
Hypoglycemia in neonatal period
Treatment of Hypoglycemia
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D10 to D15 with electrolytes 8-12 mg/kg/min IV
to maintain serum glucose leve at 120–170mg/dL
which should prevent catabolism.
 High-volume maintenance fluid 1-1.5 times
maintenance will also promote urinary excretion
of some toxic metabolites.
 If necessary, treat hyperglycemia with insulin
(0.2-0.3 IU/kg/h) to maintain glucose level in the
desired range.
Hyperammonemia
 Excess ammonia (about80% dietary and waste nitrogen)
is converted to urea in the liver through urea cycle.
 The five enzymes that make up the urea cycle are regulated
long term by the quantity of dietary protein.
 Ammonia level :
>100 mcg/dL in the neonate
> 80 mcg/dL beyond the neonatal period
is considered elevated & toxic.
Hyperammonemia
This can lead to Encephalopathy and
death OR
Devastating neurological sequelae.
Neurological sequelae and survival depend
on the length of hyperammonemic
coma(better prognosis <36h or<2days).
Hyperammonemia
 Significant hyperammonemia is observed in
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Urea cycle defect
Organic acidemia
Fatty acid oxidations defects
THAN
 Ammonia is highest in the UCDs often exceeding 1000
mcg/dL and causing primary respiratory alkalosis
sometimes with compensatory metabolic acidosis.
 Ammonia in OA, if elevated, rarely exceeds 500 mcg/dL,
and in FAO is usually less than 250 mcg/dL.
Hyperammonemia
Acidosis
Normal PH
or alkalosis
Organic acidemia
Pyruvate
metabolism
Normoglycemia
Plasma aminoacids
Urea cycle
disorders
Increased
citrulline
ASA present
Argininosuccinic
acidemia
Low/Normal
citrulline
Fatty acid
oxidation (FAO)
Increased
Citrulline
ASA absent
Urine Orotic
acid
OTC deficiency
Hypoglycemia
Hypoketosis
Citrullinemia
CPS
deficiency
THAN
The therapeutic protocol include :
 Avoidance of nitrogen intake by nasogastric infusion
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of a protein-free formula.
Adequate caloric intake (80-120 kcal/kg/d) by glucose
(10 – 20 g/kg ) .
Sodium benzoate (250-500 mg/kg/d),more recently
phenylbutyrate (250mg/kg/d) peroral
IV administration of arginine (250-500mg/kg/d)
Carnitine (250-500 kg/d)
Hydroxycobalamin ( 1mg/d)
Biotin( 10 mg/d)
Insulin may be added to utilize its anabolic effect
(0.1 -1 IU /kg/ hr if bl. glucose > 200 mg/dl )
Dialysis in patients not responding to pharmacological
therapy
Case presentation
 A 3 years old boy presented to ER with disturbed
level of consciousness of 2 days duration
triggered by fever and associated with one brief
attack of generalized tonic clonic seizures.
 The day before he ate high protein containing
food which was followed by :
period of hyperirritability and profuse vomiting
then gradual and progressive lapse in the level
of consciousness which worsen upon the
introduction of depakene to control the seizure .
 Past history : revealed two similar episodes of
disturbed conscious level :
-The first was at 7days in neonatal period .
CT at that time revealed brain edema.
-The second episode was at the age of 18
months.
 Examination :
revealed a semi conscious child with generalized
axial and limb hypotonia ,
RR 50/m.
Lab investigation
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Blood gases: ph=7.5 , Pco2=24 ,Hco3=18
Ammonia level =250mg/dl
Lactate = 3.2 mmol/l ( n < 2.1 )
Normal LFT &KFT
CBC: mild neutrophilia
 Salient features
 Disturbed conscious level
 respiratory alkalosis
 Hyperammonemia
 MS/MS revealed very high level of citrulline
 Orotic acid in urine was increased
 Final diagnosis: citrullinemia
MS/MS
Normal
Citrullinemi
a
HHH syndrome
 One year & 1mth old boy with severe failure to
thrive , excessive sleepiness .
 The condition started at the age of 4mths after
feeding baby with yogurt . He started to have
recurrent attacks of vomiting sometimes with
diarrhea ,admitted to hospital for IV fluids.
 On examination:
Fair complexion , apathy , GDD (motor
&mental) . Normal abd. Exam.
Pt . weighted 6 kg , H.C. 42 cm , length 69 cm
(all< 3rd percentile for age)
HHH syndrome
HHH cont.
 Investigations:
HGB : 10.5 , normocytic,normochromic a.
ABG : metabolic alkalosis ( repeatedly)
Ammonia : high ( repeatedly) > 300ug/dl
TMS: ( HHH syndrome)
Hyperammonemia,
Hyperornithinemia and Homocitrullinemia
HHH syndrome after therapy
Treat. hyperammonemia
ornithine supplementation ????
Metabolic Acidosis
 Among the inborn errors, the largest
group typically associated with
overwhelming metabolic acidosis in infancy
is the group of organic acidemias
 Methylmalonic acidemia,
 Propionic acidemia, and
 Isovaleric acidemia.
Important Laboratory Findings in
Organic Acidemia
 Hyperlactic acidemia
 Neutropenia and thrombocytopenia
 Hyperammonemia
 Ketosis
Emergency management of
metabolic Acidosis
 Metronidazole(10-20mg/kg) and neomycin (50mg/kg)
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reduce the level of priopionic acid and methyl malonic
acid in body fluid
Antibiotic as clindamycin and vancomycin.
Hyperammonemic episodes should be treated promptly
with Na benzoate(250mg/kg in10% glucose)
Aggressive fluid and electrolyte therapy is essential in
acute ketoacidotic crisis: 150mg-200mg/kg of 10%
glucose and isotonic NAHCO3 until acidosis is
corrected: 0.25-0.5 mEq/kg/h (up to 1-2 mEq/kg/h) IV
Consider hemodialysis ; if intractable acidosis,
(peritoneal dialysis, hemofiltration, exchange transfusion
much less effective).
Methylmalonic acidemia
 Marked failure to thrive
 severe metabolic acidosis
 ketosis
 Severe psychomotor
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retardation
Encephalopathy
Dystonia
Recurrent seizures
Peritoneal dialysis
Brain MRI
 T2w MRI demonstrating
bilateral and
symmetrical high signal
intensity lesions in the
globus pallidus
MMA
Date : 9/2010
- 2 years old male
-3mths ago he developed
recurrent attacks of G.E. &
M.A.
-Then he suffered from coma
for nearly a week ?.
-After that he developed
severe failure to thrive.
Expanded metabolic screen
using LC-MS/MS showed
MMA
Ethyl Malonic Acidemia
 A.A, the 3rd child of first degree
consanguineous parents whose
birth date is 8/2008
 The patient presented at the
age of 9 months with GDD and
intractable seizures
 Antenatal, natal and perinatal
period were uneventfull
 Clinical exam revealed,
microcephaly, microphthalmia,
frontal bossing, hypertolerism,
epicanthic folds, long filtrum
and bat ears
Ethyl Malonic Acidemia
 Neurological exam revealed
hypertonia, hyperreflexia,
positive babinski , truncal
hypotonia.
 Recurrent ecchymotic
patches on the lower limb
 No episodes of metabolic
decompensation or
metabolic acidosis
 Pt. has a normal 4 years
aged sister and mother had
one abortion
Ethyl Malonic Acidemia
 TMS result:
 elevated butyryl carnitine (C4) =4. micomol/L
cut off value =1.5 micromol/L
 Urine organic acid analysis by GC-MS
showed
 highly elevated Ethylmalonic acid
 and moderately elevated methylsuccinic acid
 no dicarboxylic aciduria and
 no lactic aciduria
Brain MRI in EMA
T2w Brain MRI showing widening of extraaxial CSF
spaces, and sylvian fissure, picture of severe brain
atrophy
TW1 Brain MRI showing
frontotemporal atrophy
 Five mths old girl coming
Ethyl malonic acidemia
from Gaza(during 25
January revolution 2011)
with recurrent attacks of
diarrhea, vomiting ,with
severe napkin dermatitis
and failure to thrive.
 Clinical exam. revealed,
microcephaly, frontal
bossing, hypertolerism,
epicanthic folds, long
filtrum and bat ears
 She weighted 3 kg , she
had hyperammonemia ,
met . acidosis .
 TMS : Ethyl malonic
acidemia
Pyroglutamic aciduria
 3 mths old boy ,1 st baby
 Admitted to PICU due to
DCL , shortness of
breath, increased
yellowish discoloration
of skin after severe
attacks of vomiting for
previous 2 days not
associated by diarrhea.
History
The condition started at the age of 5 days by
Jaundice which was diagnosed as physiological ,
no treatment .
For the following 3 month the mother noticed
gradual abd . distention and no improvement in
colour .
On examination
the baby was lethargic with tachypnea ,
hepatomegaly (span 10cm ) and cholestatic
jaundice ( T=9.6 , d=5.2).
He was ventilated but it was difficult
to be weaned from vent. as he developed cardiac
problems as severe bradycardia and arrest.
 Investigations
 CBC: HB 10gm% , WBC :24,000
 Bil total: 9.6 Direct :5.2 mg/dl
 ALT :115 . PT :26, INR:2.9
 Urea :30 , creatinine:0.7
 CRP: 12
 ABG : variable with increased anion gap 59
 Bl. Ammonia : 607---- 230---303 ug/dl
 MS/MS : Pyroglutamic aciduria
 Urine organic acids was done
The baby was treated
with Na benzoate and
glutathione analogs,
vit C and vit E.
He started to gain
consciousness and he
was weaned from the
vent. The jaundice
and hepatomegaly
decreases .
Pyroglutamic aciduria
after therapy
• 2.8 years old
• At the age of 2y , she developed
recurrent attacks of convulsions and
was treated with antiepileptic drugs
• At 2.1 y, she suffered recurrent
attacks of RD with metabolic
acidosis , no hypogycemia ,no hep.
• Then she went in coma for 1 d.
• Bl Ammonia level was elevated
so she received Na benzoate
•She improved for 2w then amm.
increased again.
• MS/MS was normal
• ALT ,AST were 2-3 times normal
• There was no hypoglycemia during
the illness
•Liver span 10 cm, firm
Liver biopsy 10/8/2010
metabolic LD ---- GSD
Hepatocellular necrosis, acute or
subacute
GALACTOSEMIA
 There are three known enzymatic errors .
 The most common defect is decreased activity
of galactose 1-phosphate uridyltransferase
(GALT)
 Clinical manifestations include :
lethargy, hypotonia, jaundice.
Hypoglycemia, elevated liver enzymes
Coagulopathy
 Diagnosis
 Reducing substances in infants urine with
simultaneous normal or low blood sugar while
the infant is being fed breast milk or a formula
containing lactose.
 enzyme activity measurement in erythrocytes .
 Prenatal diagnosis by direct measurement of the
enzyme activity(GALT).
GALACTOSEMIA
 Treatment
 The main is lactose-free formula followed by
dietary restriction of all lactose-containing foods
later in life.
 Untreated infants may have severe growth
failure, mental retardation, cataracts, ovarian
failure, and liver cirrhosis.
 Despite early and adequate intervention, some
children still may develop milder signs of these
clinical manifestations.
Hereditary fructose intolerance (HFI)
 Alternative names
 Fructosemia; Fructose intolerance; Fructose aldolase B-
deficiency; Fructose 1, 6 bisphosphate aldolase
deficiency
 An autosomal recessive disorder
 Although glucose may still be released through
the breakdown of glycogen ,it cannot be
synthesized from gluconeogenesis, resulting in
severe hypoglycaemia
Hereditary fructose
intolerance (HFI)
 Tests that confirm the diagnosis
 Positive urine test for reducing substances .
 Hypoglycemia , especially after receiving
fructose/sucrose .
 Abnormally high amounts of amino acids and salts
in urine
 Enzyme studies
 Treatment
 Complete elimination of fructose and sucrose from
the diet is an effective treatment for most patients.
TYROSINEMIA TYPE I (TTI)
 Autosomal recessive disorder
 Incidence of 1:100,000 to 1:120,000.
 The defect is in fumaryl acetoacetate hydrolase,
resulting in accumulation of metabolites such as
fumarylacetoacetate and malelylacetoacetate which
are alkylating agents that cause damage to DNA and
predisposition to HCC.
 One of the byproducts of these metabolites is succinyl
acetone, which is a diagnostic marker for tyrosinemia .
 Presentation of TTI
 Include :
 Acute liver failure, chronic liver disease, HCC.
 Renal tubular dysfunction.
 Episodic porphyria-like neurological episodes(42% of
patients )caused by succinyl acetone inhibiting the
metabolism of aminolevulinic acid.
 Neurological crises began at a mean age of 1 year.
Episodes included severe pain with extensor hypertonia,
vomiting or paralytic ileus, muscle weakness, and selfmutilation.
TYROSINEMIA TYPE I (TTI)
 Diagnosis
 Serum amino acid patterns may exhibit high
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levels of tyrosine, phenylalanine and
methionine.
Generalized aminoaciduria.
High levels of alpha-fetoprotein are observed.
succinyl acetone in urine and serum is a
diagnostic marker for tyrosinemia.
Enzyme measurement in lymphocytes &RBC
Product ion scans of derivatized SA (top)
and 5,7dioxooctanoic acid (internal
standard; bottom)
and fragmentation of SA-hydrazone (inset).
A simple method for quantifying SA in dried blood spots
has been described by Allard et al.,2004 .
Inclusion of SA in our existing screening program could be
achieved with little additional manual work.
 The medical management of TTI
 Has changed considerably with the introduction of
2-(2-nitro-4-trifluoromethylbenzol)-1,3cyclohexendiome (NTBC) in 1992.
 NTBC blocks the second step in tyrosine
degradation, thus preventing formation of the
alkylating metabolites.
 Currently, the indication for transplantation
includes treatment failure or development of HCC.
WILSON'S DISEASE
 An autosomal recessive disease.
 The specific molecular defect resides within a
copper-transporting ATPase encoded by a
gene on chromosome 13.
 Affected patients exhibit impaired biliary
excretion of copper; this leads to copper
accumulation in the liver , brain, cornea, and
kidneys.
 Clinical presentation
 The most common presentation is that of
postnecrotic cirrhosis with hepatic dysfunction
and portal hypertension or chronic active
hepatitis.
 The disease may manifests as fulminant
hepatic failure; with massive liver necrosis,
coincident hemolysis .
 Diagnosis
 A useful screening test is low serum ceruloplasmin.
It is < 20 mg per dl in 85% of patients.
 The presence of Kayser-Fleischer rings.
 Increased urinary excretion of copper.
 Elevated liver copper on biopsy.
Patients with > 250 µg copper per gram of dry liver
tissue are considered to have Wilson's disease.
 Measurement of urinary copper excretion in
response to oral penicillamine challenge .
The Kayser–Fleischer ring around the
periphery of the cornea caused by
deposition of copper in Descemet's
membrane
Hyperintensities in the bilateral basal
ganglia and thalami shown by T2-weighted MRI
of the brain
Das SK and Ray K (2006) Wilson's disease: an update
Nat Clin Pract Neurol 2: 482–493
 Treatment
 Copper chelation improves survival. Treatment
includes D-penicillamine, triethylene tetramine
dihydrochloride (tientene; generally used in Dpenicillamine-intolerant patients), and oral zinc.
 Once initiated, therapy must be continued for life;
discontinuation can result in rapid deterioration.
 liver transplantation in patients with fulminant
hepatic failure or decompensated cirrhosis, provides
effective therapy.