Hepatic function BSC 1 21 Flashcards
the importance of alpha amino groups
The presence of the α- amino group keeps amino acids safely locked away from oxidative breakdown.
Removal of α- amino group is an obligatory step in the catabolism of all amino acids
Once removed this nitrogen can be incorporated in to other compounds or excreted, with the carbon skeleton being metabolized
Different animals excrete excess nitrogen as ammonia, uric acid, or urea.
Biosynthesis of urea: 4 stages
- transamination (removal of alpha amino group)–> glutamate
- deamination –> ammonia
- transported to liver as glutamate glutamine or alanine
- detoxification by Urea cycle reactions
What does GDH do?
from glutamate makes NH4+
2 mechanisms of transport of ammonia to liver
The first uses glutamine synthetase to combine glutamate with ammonia
The second , used primarily by muscle, involves transamination of pyruvate to Alanine
6 amino acids that participate in urea formation
6 amino acids participate in urea formation, which are:
Ornithine Citrulline Aspartic acid Argino succinic acid Arginine and N-Acetyl Glutamate
CPS-1 deficiency
Carbamoyl Phosphate synthetase (CPS-1) deficiency
Along with OTC deficiency, deficiency of CPS1 is the most severe of urea cycle disorders.
Individuals with complete CPS1 deficiency rapidly develop hyperammonemia in the newborn period.
Children who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia
OTC deficiency
Absence of OTC activity in males ia as severe as CPSI deficiency.
Approx 15% of carrier females develop hyperammonemia during their lifetime and may require chronic medical management
Citrulinemia type 1 deficiency
The hyperammonemia in this disorder is quite severe.
Affected individuals are able to incorporate some waste nitrogen into urea cycle intermediates, which makes treatment easier
ASL deficiency
This disorder also presents with rapid onset hyperammonemia in the newborn period.
This enzyme defect is past the point in the metabolic pathway at which all the waste nitrogen has been incorporated into the cycle.
Treatments requires only supplement of arginine.
ASL deficiency is marked by chronic hepatic enlargement and elevation of transaminases
Affected individuals may go to coma and may have significant developmental disabilities
Arginase deficiency
Arginase deficiency (hyperargininemia: ARG deficiency) This disorder is not typically characterized by rapid onset hyperammonemia Affected individuals develop progressive spasticity and can also develop tremor, and ataxia. Growth is affected
clinical manifestations of urea cycle deficiency
Infants with a urea cycle disorder often appear normally initially but rapidly develop
Cerebral edema and signs of lethargy, anorexia, hyperventilation or hypoventilation
Slurring of the speech, blurring of the vision , seizures, neurological posturing and coma.
Laboratory diagnosis
The diagnosis of a urea cycle disorder is based on evaluation of clinical, biochemical, and
Molecular genetic data
A plasma ammonia conc of 150 mmol/L or higher is a strong indication for the
Presence of UCD
Plasma conc of citrulline helps determone between the proximal and distal urea cycle
Defects, as citrulline is the product of the proximal enzymes (OTC and CPS1) and a
Substrate for the distal enzymes (ASL, ARG)
Urinary orotic acid is measured to distinguish between CPS1 deficiency and OTC deficiency
What is it when you see high uracil or orotic acid?
OTC deficiency
Hartnup disease
Hartnup disease is inherited as an autosomal recessive trait.
Heterozygous are normal.
Consanguinity is common.
Mutations in the SLC6A19 gene which encodes the Bo AT1, sodium dependent,
Chloride independent, neutral amino acid transporter.
Cause a failure of the transport of the neutral amino acids in the small intestine and renal tubules.
Excessive tryptophan and other aa excreted in urine
–> not enough B vitamin complex, esp. under stress
TREATMENT: High Protein Diet.
