Download Cyclosporine Induced Myopathy 9/1/09 Justin A. Crocker, MD

Ornithine Transcarbamylase
Deficiency (OTCD)
9/1/09
Justin A. Crocker, MD
What is it?
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X-linked disorder of the mitochondrial urea cycle
Occurs 1 in every 80,000 people.
associated with hyperammonemia affecting mainly
male patients.
Frequently, they die during the neonatal period,
unless an early diagnosis and intensive
management are carried out.
Some patients with partial enzyme deficiencies
might be asymptomatic until adulthood
Heterozygous female patients exhibit a wide range
of clinical manifestations.
Urea cycle revisited
Pathophys
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OTCD leads to the impaired condensation of carbamyl
phosphate and ornithine to form citrulline. This impairment leads
to reduced ammonia incorporation which, in turn, causes
symptomatic hyperammonemia and excess of both substrates for
the reaction.
Under normal circumstances urea cycle occurs in hepatic
mitochondria. However when excessive carbamyl phosphate it
finds its way into the cytosol where it functions as substrate for
the carbamoyl phosphate synthetase (CPS) reaction. This results
in orotic acid, which is a normal intermediate in the very tightly
regulated pyrimidine biosynthesis. In OTCD neither conversion of
CPS to orotate nor hepatic leakage of ornithine can prevent the
rapid development of hyperammonemia.
Glutamine accumulation in the brain from hyperammonia is likely
culprit of cerebral edema.
Causes
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Mechanisms that can tip the nitrogen balance
appear to break down into three categories:
(1) nitrogen turnover and nitrogen load from
catabolism or sudden protein processing
(2) diminished access to processing in the
liver
(3) the genetic capacity of the urea cycle to
handle the nitrogen load
Nitrogen turnover and nitrogen load
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Rapid weight loss and poor nutritional intake
Gastric bypass surgery
Internal bleeding or damage
Fracture
Surgical damage
Viral illness or other generalized stress
Postpartum period
Dramatic increase/decrease in habitual protein intake
High protein diet strategies
Change in food access or preparation
Malabsorption conditions
Medications affecting protein catabolism
Intravenous or high-dose glucocorticoids
Chemotherapy
Diminished access to
processing in the liver
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Vascular shunting of blood from liver
Portacaval shunt
Varicocele shunting from cirrhotic liver
Decrease in available hepatocyte pool
Chronic cirrhosis
Acute chemical or viral damage to the liver
Genetic predisposing conditions
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Genetic defects in enzyme/transporter function of
the urea cycle components or decreased function
polymorphisms
Chemical or toxic affect on enzyme function
5-pentanoic acid (Jamaican vomiting sickness)
Valproic acid
Chemotherapeutic agents (cyclophosphamide)
Comorbid metabolic conditions
Organic acidemias
Fatty acid oxidation defects
Diagnosis
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Family history, dietary history, episodic
nonspecific symptoms, response to
withdrawal of protein
Evaluate for possible precipitating events as
outlined above: GI bleeding, trauma, viral
illness, pregnancy test, offending
medications, liver disease
Plasma amino acids and urine organic acids
Genotyping with skin fibroblasts
Management
Physically remove NH3
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Usually done by dialysis or some form of hemofiltration.
Begin at the highest available flow rate as soon as possible.
Dialysis is the most effective means of ammonia removal, and
the rate is dependent on the flow through the dialysis circuit
In severe cases of hyperammonemia, provision for hemofiltration
following the dialysis should be made until the patient is
stabilized and the catabolic state is reversed.
Some patients will reaccumulate ammonia after their initial round
of dialysis and may require additional runs.
Most patients will have a slight rise in ammonia after dialysis
because removal by scavengers and the liver will not be as
effective. This slight rise usually does not necessitate repeat
dialysis.
Reverse the catabolic state
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Fluids, dextrose, and fat emulsion (Intralipid) should
be given.
Insulin and glucose to artificially suppress the
catabolic state is useful in profound catabolic states
protein should be temporarily removed from diet
Supplementation of arginine serves to replace
arginine not produced by the urea cycle and
prevents its deficiency from causing additional
protein catabolism.
Pharmacologic scavenging of excess
nitrogen.
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Loading dose followed by a maintenance infusion of
sodium benzoate/sodium phenylacetate
Sodium benzoate combines with glycine to make
hippurate, which is excreted by the kidneys
Sodium phenylacetate combines with glutamine to
make phenacetylglutamine, which is also excreted in
the urine.
The body replaces these amino acids using excess
nitrogen.
Additional issues
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Use of osmotic agents such as mannitol is not felt to
be effective in treating the cerebral edema of
hyperammonemia
IV steroids and valproic acid should be avoided
Antibiotics and a septic work-up are indicated to
treat potential triggering events
Rapid response to the hyperammonemia improves
outcome.
Symptomatology centers around cerebral edema
and pressure on the brain stem.
Long-term
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Avoid similar triggering events. In particular,
intravenous steroids for asthma or valproic acid are
contraindicated.
Long-term diet modification with nutritional oversight
is often necessary
Avoid dehydration
Special precautions must be taken to avoid
catabolism during subsequent illnesses or surgeries,
as well as during any event resulting in significant
bleeding or tissue damage.
It is important to provide genetic counseling to
assess risk to other family members.
References
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Bajay SK, Kurlemann G, Schuierer G, et al. CT and MRI in a girl
with late-onset ornithine transcarbamylase deficiency: case
report. Neuroradiology. 1996;38:796-799.
Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis,
pathophysiology and therapy. Advanced Pediatrics. 1996;43:127170.
Lien, J, Nyhan, WL, et. al. Fatal Initial Adult-Onset Presentation
of Urea Cycle Defect, Archives of Neurology. 2007;64(12):17771779.
Summar, ML, et. Al. Unmasked Adult-Onset Urea Cycle
Disorders in the Critical Care Setting. Critical Care clinics.
2005;21.
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