Urea cycle

Question 1

CPS1 Def. (Hyperammonia Type I)

Answer 1

• ammonia intoxication Sx:
  
  • tremors
  • slurring of speech
  • somnolence
  • vomiting
  • cerebral oedema
  • blurring vision
• Highly toxic for brain due to:
  
  • GDH & Glutamine Synthetase deplete the brain of NT glutamate & GABA
  • High glutamine levels in brain cells leads to cerebral oedema
• Rx:
• L-Arg supplementation
  
  • Rationale: Arg stimulates formation NAG (also used for treat def. before arginase)
  • promotes excretion of citrulline & argininosuccinate

Question 2

General management of Hyperammonemia

Answer 2

• Benzoic acid
  
  • combines with Gly
  • requires activation to CoA derivative
  • product is Hippuric acid
  • Excretion of 1 N (not efficient)
• Phenylbutyrate (prodrug)
  
  • combines with glutamine (not smelly)
  • product is Phenyacetylglutamine (active form but smelly)
  • Excretion of 2 N
  • conversion to CoA derivative Phenylacetyle-CoA
• Dialysis: Acute
• Low protein/high carb diet to minimize N intake
• Prescribe alpha-Keto acids (expensive)
• Long-term: Liver transplant

Question 3

OTC Def (Type II Hyperammonemia)

Answer 3

• X-linked def. of mitochondrial OTC
• usually seen in males & more severe in males
• Dx:
  
  • hyperammonemia
  • Orotic Aciduria
  • decreased BUN
  • high Gln levels
• Sx:
  
  • cerebral oedema
  • lethargy
  • convulsions
  • coma
  • death

Question 4

Argininosuccinate Synthetase Def (Classic Citrullinemia)

Answer 4

• Dx:
  
  • hyperammonemia
  • very high citrulline (serum & urine)
• Rx:
  
  • Arg admin
  • enhances urinary citrulline excretion
  • sometimes allows urea cycle to progress due to high levels of substrate

Question 5

Argininosuccinate Lyase Def (Argininosuccinic aciduria)

Answer 5

• DDx of hyperammonemia
  
  • elevated plasma & cerebral spinal fluid argininosuccinate
  • moderately high levels of citrulline
  • argininosuccinate detected in urine
• Rx: Arg supplement; allows urinary excretion of argininosuccinate
  *

Question 6

Arginase Def (Hyperargininemia)

Answer 6

• DDx: elevated serum ammonia & elevated arginine
  
  • blood NH3 levels not as high as other UCD
• Rx : diet of essential aa excluding Arg
• Sx
  
  • adult onset associated with neuro problems

Question 7

Acquired Hyperammoneia

Answer 7

• not due to enzyme def
• Liver disease due to:
  
  • viral or drug induced hepatitis
  • alcoholic cirrhosis
• ammonia produced in intestine directly enters circulation
• results in neurotoxicity
  
  • E & osmotic effect: alpha-KG converted to Glu via GDH
    
    • decreased TCA activity
    • decreased ATP synthesis
    • subsequent reduced Na+/K+ ATPase activity leads to:
      
      • changes in osmotic pressure
      • eventual neuronal cell death
  • NT effect: Glu converted to Gln via Glutamine Synthetase
    
    • higher Gln levels
    • reduced Glutamate and GABA in brain when NH3 abundant
    • high Glutamate causes cerebral edema

Question 8

Management of Acquired Hyperammonemia

Answer 8

• Lactulose
  
  • disaccharide resistant to digestion in small intestine
  • nl bacterial flora in colon produce lactic acid
  • acid conditions favour NH4+ formation
  • promotes more NH3 in lumen
• Neomycin: reduction of bacterial urease in gut