Urea Cycle

Purpose

Preparation of waste nitrogen for disposal by the kidneys.

Metabolic breakdown of nitrogen compounds produces ammonia.
Enzymes in the liver cells convert ammonia to urea which can be
excreted by the kidneys.

Nitrogen Metabolism
Transamination

Transfer of a nitrogen-containing amine group from an AA in

exchange for a ketone group on another acid.
Alanine and alpha-ketoglutaric acid are converted to pyruvic acid
and glutamic acid.
Catalzyed by alanine aminotransferase (ALT) and co-factor
vitamine B6.
Measurement of ALT activity is used as marker for hepatocyte
injury; when hepatocytes are injured, serum level of ALT rise.

Oxidative Deamination

Glutamic acid is converted to ammonia and alpha-ketogluatric

acid.
Ammonia enters the urea cycle.

Urea Cycle

2 NH2 + CO2 +3ATP Urea + H2O +3ADP

Metabolic Disorders
Caused by:

Accumulation of excess amounts of toxic metabolites.

Decreased amounts of necessary metabolites.
Both.
Accumulation of ammonia is called hyperammonemia.

Result of High Blood Ammonia

Disruption of ion gradients, neurotransmitters, transport of

metabolites, mitochondrial function and alterations in the ratios
of alpha-ketoglutarate/glutamate/glutamine.
Elevated ammonia levels can cause cerebral edema.

Symptoms

Early symptoms include irritability, lethargy and vomiting.

As ammonia levels rise patients may develop stupor, seizures
and posturing.
As symptoms progress patients may develop cerebral edema,
increased intracranial pressure and brain stem herniation that
result in apnea and death.

Causes of Hyperammonemia
Acquired

Acute liver failure

Chronic liver failure
Reyes syndrome

Inherited

Organic acidemia.
Fatty acid oxidation disorders.
Urea cycle disorders.

Clinical Course

Total absence of any of the first 4 enzymes of the urea cycle

cause accumulation of ammonia that result in rapid onset of
symptoms.
Milder or partial absence may only result in symptoms during
times of illness or stress associated with decreased caloric intake
and increase muscle protein breakdown.
Symptoms may occur with increased protein intake.

Clinical Findings Early vs Late Onset

Newborns may appear normal but soon after feedings begin

develop vomiting, irritability and progressive lethargy, which
leads to seizures, hypotonia, respiratory distress, coma and
death if untreated.
Older infants, children, adults may have irritability, herpactivity,
protein avoidance, delayed development, intellectual
imparement, vomiting, seizures.

Treatment

Dietary restriction
Hydration, IV glucose

Avoid drugs known to cause liver damage.

Nitrogen removal by exchange transfusion, dialysis, sodium
phenylbutyrate, sodium benzoate.
Liver transplant.
Gene therapy.