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INTRODUCTION
The
organic acidemias comprise a group of metabolic disorders in which
the defect produces an accumulation of organic acids*. The central
emergency features of the organic acid disorders are profound metabolic
ketoacidosis and hypoglycemia. The inheritance of Isovaleric
acidemia is autosomal recessive. It is often referred to as the "sweaty
foot syndrome" due to the characteristic odor body and body fluids
odor produced by it.
*Organic acids are distinguished from amino acids in that they
do not contain nitrogen.
PATHOPHYSIOLOGY
Catabolic
stress such as normal perinatal catabolism or febrile illness (e.g.
infection) produces endogenous proteolysis. The released amino acids
add to the amino acid pools and are degraded within the relevant pathways,
producing increased amounts of the organic acid intermediates. When
excessive protein is ingested, a similar increase in available amino
acids occurs. When there is a metabolic defect after the amino acid
has lost its nitrogen in the course of degradation (see the pathway
above), the esterified organic acid-CoA accumulates. Much of the esterified
organic acid is converted to the parent organic acid and other organic
acid metabolites.
The increased
metabolite measured in urine and/or blood in these disorders is the
organic acid per se and, in urine, the related metabolites. The increased
organic acids overwhelm the body's acid-base balance, resulting in
metabolic acidosis. This metabolic stress produces an increased need
for cellular energy, which is provided by enhanced degradation of
glucose, resulting in hypoglycemia. The hypoglycemia is exacerbated
by inhibition of gluconeogenesis induced by one or more of the accumulated
organic acids. The hypoglycemia sets in motion hormonal changes that
cause release of free fatty acids from adipose tissue. The fatty acids
are transported into mitochondria as carnitine conjugates where they
are b-oxidized to ketones, producing ketosis. The increased organic
acid also inhibits the urea cycle producing hyperammonemia, glycine
degradation producing hyperglycinemia, and hematopoeisis resulting
in neutropenia. Hence, the constellation of laboratory findings in
these organic acid disorders:
Ketoacidosis
Hypoglycemia
Neutropenia
Hyerammonemia
Hyperglycinemia
The
ketoacidosis, hyperammonemia and hypoglycemia can explain the lethargy
and obtundation. The ketoacidosis also produces vomiting. Mobilization
of free fatty acids from stores to the liver produces a fatty liver.
The increased organic acids may also be toxic to hepatocytes.
PRESENTATION
- Lethargy
- Vomiting
- Hepatomegaly
- Hypoglycemia
- Metabolic acidosis
- Hyperammonemia
- Neutropenia
- "sweaty
foot" odor
There
are two types of presentation, depending on the severity of the metabolic
defect. The neonatal form presents within the first days of life with
a life-threatening picture of severe lethargy progressing to obtundation.
The infantile or late-onset form has a more insidious presentation
with failure to thrive, developmental delay, and perhaps other neurologic
features such as seizures and spasticity. These children can decompensate
acutely during catabolic stress, usually brought on by infection.
In both presentations, the pungent odor may be prominent on the body
and in the blood.
DIAGNOSIS
ASSESSMENT
- STAT chemstrip to check for hypoglycemia
- vital signs, cardiovascular stability
- hydration status
- presence of fever; signs of infection
- hepatomegaly
- neurologic status; evidence of increased intracranial pressure
LABS
Blood
- (arterial) blood gas
- electrolytes, measured CO2, glucose
- ammonia (in ice STAT to lab)
- AST, ALT, AlkPO4, PT, PTT
- plasma amino acids
- serum carnitine
- CBC, differential WBC count, platelets
Urine
- urinalysis for specific gravity and ketones
- urine for organic acids
- as needed, cultures of blood, urine and throat
NOTE, organic acids and ammonia are toxic to the brain and accumulations
of these may result in cerebral edema. Caution should be exercised
when considering the need for a lumbar puncture.
Parents of children with diagnosed metabolic disorders know the
early signs of decompensation in THEIR children. Listen to them !!!
THERAPY
The
treatment for acute metabolic decompensation in these disorders includes:
1. Hydration
2. Correction of the biochemical abnormalities (metabolic acidosis,
hyperammonemia, hypoglycemia)
3. Reversal of catabolism/promotion of anabolism
4. Elimination of toxic metabolites
5. Treatment of the precipatating factor when possible (e.g. infection,
excess protein ingestion)
6. Cofactor supplementation
7. Consider hemodialysis
1. HYDRATION
Intravenous fluids should be administered
with enough glucose to prevent further catabolism and sufficient
alkali to treat the acidosis.
Consider running 10% dextrose with
a piggybacked biocarbonate infusion of 1 † - 1 á times the
maintenance rate. Piggybacking allows individual adjustment/titration
of the IV solutions. Add KCI if renal
function is not compromised.
Ringer's lactate should NEVER be
used for fluid/electrolyte therapy in a child with a known/suspected
metabolic disorder.
2. CORRECTION OF BIOCHEMICAL ABNORMALITIES
(i) Hypoglycemia - if hypoglycemic, administer 1-2 g/kg of
glucose IV STAT;
follow with (at least) a 10% glucose solution
(ii) Metabolic acidosis - administer NaHCO3
as a bolus (1 mEq/kg) if acutely acidotic with pH < 7.22
or biocarb level < 14, followed by a contiguous
infusion. If hypernatremia becomes a problem, reduce
the rate of the Na bicarb drip; replace with
K acetate.
(iii) Hyperammonemia - the elevated ammonia reflects a secondary
inhibition of the urea cycle.
As treatment for the organic acidemia
proceeds, the ammonia level should diminish. For extremely
elevated ammonia (> 600 umol/L) or
persistently elevated levels, dialysis should be considered
(see Part 7).
3. REVERSAL OF CATABOLISM/PROMOTION OF ANABOLISM
(i) GLUCOSE: Catabolism can be diminished by providing large amounts
of glucose (10% dextrose at
maintenance or above), thereby surpassing hepatic
glucose production. This therapy should be started
as soon as possible after the patient presents
to the emergency room.
(ii) PROTEIN: All natural protein (containing all amino acids) should
be withheld for 48-72 hours
while the patient is acutely ill.
Amino acid therapy may be very beneficial
in facilitating clinical improvement but should be implemented
only under the supervision of a physician/nutritionist
with expertise in metabolic management. Providing
an amino acid preparation which includes only "nonoffending
amino acids" which are degraded by the
defective biochemical pathway (i.e., avoiding leucine)
during the initial crisis period may not only stimulate
anabolism but help prevent significant weight loss.
If the patient is not significantly
neurologically compromised, these preparations can be provided enterally.
Specialized formula preparations for
isovaleric acidemia provide the appropriate mix of amino acids. Where
there exists a high risk for aspiration or
a contraindication to enteral feeding, consideration should be given
to providing a specialized parenteral amino
acid solution available through certain TPN pharmacies.
(iii) LIPID:
Intralipid may be given to supply extra
calories.
(iv) CALORIES:
A goal for calories during a period
of decompensation, in order to support anabolism, would be about
20% greater than ordinary maintenance needs.
One must remember that withholding natural protein from
the diet also eliminates this source
of calories and should be replaced by other dietary or nutritional
sources.
(v) INSULIN:
Insulin is a potent anabolic hormone,
promoting protein and lipid synthesis. While large scale or
objective studies do not exist to prove its
value in the treatment of metabolic crises, theoretically it would
appear to be a useful adjunct in reversing
unwanted catabolism and facilitating the uptake of offending
amino acid precursors.
4. ELIMINATION OF TOXIC METABOLITES
Correction of acute metabolic perturbations
(acidosis, hypoglycemia) may help clear some of the factors
contributing to the encephalopathy associated with acute metabolic
crises. However, the presence of large
quantities of toxic intermediate metabolites, believed to be toxic
to the brain as well, are not cleared with
glucose or bicarbonate, or rapidly with hydration. Consideration should
be given to providing the means to help
facilitate the excretion of these compounds:
(i) L-CARNITINE
Free carnitine levels are
low in the organic acidemias because of increased esterification with
organic
acid metabolites. While carnitine supplementation
is controversial, there are case reports where it has
proven helpful during acute crises. If administered,
it should be mixed in 10% glucose and run as an
infusion to provide 100 mg/kg per 24 hour period
(max = 5 grams/day). When oral fluids are tolerated,
carnitine may be administered PO at a dose of 100
mg/kg/day.
(ii) L-GLYCINE
While glycine supplementation
is controversial, it may prove helpful during acute crises for detoxifying
toxic acyl-CoA accumulates. Glycine may be
administered PO at a dose of 150-300 mg/kg/day.
(iii) HEMODIALYSIS:
When a patient is comatose,
dialysis is indicated to facilitate a more rapid clearance of metabolic
toxins
which would otherwise be dependent on
renal excretion, a much slower process (see 6. HEMODIALYSIS).
5. TREATMENT OF PRECIPATATING FACTORS
Infection should be treated
vigorously when possible. Note that neutropenia (and thrombocytopenia)
frequently accompany metabolic decompensation. Bone marrow recovery
is expected once the levels of toxic
metabolites diminish significantly
6. HEMODIALYSIS
Hemodialysis is indicated
in cases with -
- intractable metabolic acidosis
- unresponsive hyperammonemia ( > 600 µmol/L)
- coma
- severe electrolyte disturbances (usually iatrogenic)
The Renal Service should be alerted early on in
the hospital course.
MONITORING THE PATIENT -
Clinical parameters -
Mental status
Fluid balance
Evidence of bleeding (if thrombocytopenic)
Symptoms
of infection (if neutropenic)
Biochemical
parameters -
Electrolytes, measured CO2, glucose, ammonia,
blood gases q 4-6 hours
CBC with differential, platelets
Urine for ketones q void; follow specific gravity
RECOVERY
The patient should be kept NPO
until his/her mental status is more stable. Anorexia and nausea/vomiting
during the acute crisis period makes a significant oral intake unlikely.
If the patient is not significantly neurologically compromised, consideration
should be given to providing the patient (PO or by NG tube) with a
modified formula preparation containing all but the offending amino
acids (see THERAPY, Part 3).
When
the infant/child is able to take fluids orally/per ng/gastrostostomy
tube, please contact the Metabolism fellow/staff or the Metabolism
nutritionists, since each patient has a unique, modified diet. Each
day, the nurses caring for the patient should review the menu with
the parents or the nutritionists to avoid dietary mistakes; these
do happen and can be disastrous in the peri-crisis period.
In conjunction
with this protocol, please call or have paged the genetics metabolism
fellow on call, or failing this, the metabolic attending on call at
your hospital or nearest pediatric tertiary care center
Last
Updated: Wednesday, September 6, 2006
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