Hyperammonemia is a medical condition characterized by an abnormally elevated level of ammonia in the bloodstream. It is caused by defects in the urea cycle which is responsible for detoxifying ammonia produced from protein catabolism. Symptoms range from lethargy and vomiting to seizures and coma. Diagnosis involves tests of blood and urine amino acid and organic acid levels as well as genetic testing. Treatment focuses on restricting protein intake, supplementing with alpha-ketoacid derivatives, and administering drugs to conjugate ammonia into excretable compounds to lower blood ammonia levels.

1. Hyperammonemia

2. Contents
• Introduction
• Causes
• Types
• Diagnosis
• Management
• Summary

3. Introduction
• Increase ammonia in blood
• Normal level of ammonia (10-40μmol/L)very low, compared to BUN.
• Medical emergency-neurotoxic
• Biochemical sign of failure of liver & defects in urea cycle enzymes.
• Symptoms- tremors, slurring of speech, somnolence, vomiting,
cerebral edema, blurring of vision.
• Leads to loss of consciousness,coma and convulsions, and may be
fatal

4. Explanation for ammonia toxicity
• Withdrawal of Alpha ketoglutarate to form glutamate ( catalyzed by
glutamate dehydrogenase) and then glutamine (catalyzed by
glutamine synthetase)
• Leads to lower concentrations of all citric acid cycle intermediates
• Reduced generation of ATP
• Ammonia also inhibits oxidative decarboxylation of Alpha
ketoglutarate

5. Causes
• Enzyme defects in urea cycle
• Organic acidurias
• Congenital lactic acidosis
• Hepatic encephalopathy; liver failure
• Cor pulmonale
• Pulmonary emphysema
• Renal failure

6. Types
1. Acquired Hyperammonemia (Hepatic Coma)
• Liver disease is the common cause in adults
# Hyperammonemia – characteristic feature of liver failure.
#The condition known as – portal systemic encephalopathy
Cirrhosis of Liver – collateral circulation – Portal blood shunted into
Systemic circulation
Ammonia Urea
• It may also be due to viral hepatitis or hepatotoxins(alcohol)

7. Types
2.Congenital hyperammonemia
Genetic deficiencies of enzymes of urea cycle – overall incidence-
1:25,000 live births
• X linked OTC deficiency – most common
• All other urea cycle disorders - autosomal recessive
Urea cycle disorders are characterized by hyperammonemia,
encephalopathy and respiratory alkalosis.

9. • Four of five metabolic diseases, results in accumulation of precursors
of urea principally ammonia and glutamine.
• Ammonia intoxification is most severe when the metabolic block
occurs at reactions 1 and 2 .
• #note
Hyperammonemia seen with arginase deficiency is less severe .

10. Carbomyl Phosphate Synthetase I deficiency
Hyperammonemia type I
Comparatively rare
Incidence is 1 in 100000
Severe Hyperammonemia; very high ammonia levels in blood.
Autosomal recessive
Mental retardation.

11. N- Acetylglutamate Synthetase deficiency
• N acetyl glutamate synthetase catalyzes the formation of
N Acetylglutamate from glutamate and acetyl CoA
Note: clinical and biochemical features of of NAGS deficiency are
indistinguishable from those arising from a defect in carbamoyl
phosphate synthase 1.

12. Ornithine transporter deficiency
Hyperornithinemia, hyper ammonemia and homocitrullinuria
HHH Syndrome
Mutation of ORNT1 gene – ornithine permease
Failure to import ornithine from cytoplasm to mitochondria
Decreased urea in blood
Autosomal recessive condition

13. Ornithine Transcarbomylase deficiency
Hyperammonemia type II
Most common and X linked trait.
High ammonia level in blood
Levels of glutamine are elevated in blood ,cerebrospinal fluid and urine.
Orotic aciduria – channeling of carbomyl phosphate into pyrimidine
synthesis.
Glutamate+NH3 glutamine synthetase. Glutamine

14. Arginosuccinate synthetase deficiency
Citrullinemia
Characterized by hyperammonemia ,citrullinuria and citrullinemia
High blood levels of ammonia and citrulline
1-2 g of citrulline are excreted daily.
Autosomal recessive
Incidence is 1 in 70000

15. Arginosuccinate lyase deficiency
Arginosuccinic aciduria
leads to arginosuccinic aciduria and therefore metabolic acidosis.
Hyperammonemia less severe.
Arginosuccinate is elevated in CSF and excreted in urine.
lncidence is 1:75000
Typical clinical feature : friable tufted hair ( trichorrhexis nodosa)

16. Arginase deficiency
Hyperargininemia
• Mild variety with accumulation and excretion of arginine
• Hyperargininemia and argininuria are seen
• Symptoms like other urea cycle disorders do not appear until age
2 to 4 years.
• Incidence is 1 in 100000

17. Signs and Symptoms
Early onset hyperammonemia(neonates)
• Normal appearance at birth
• Hypothermia
• Lethargy
• Irritability
• feeding disruption ( increases catabolism)
• Vomitting
• Seizures
• Hyperventillation; grunting respiration

18. Signs and Symptoms
Late onset hyperammonemia(later in life)
• Intermittent ataxia
• Intellectual impairment
• Gait abnormality
• Recurrent reye syndrome
• Tend to avoid protein in their food
• Epilepsy

19. Diagnosis
*Family history
*Physical examination: No findings
*Lab tests:
• Arterial blood gas analysis
• Serum aminoacid levels
• Urinary orotic acid levels
• Urinary ketone tests
• Plasma and urinary organic acid levels
• Enzyme assays

20. Diagnosis
*Molecular genetic testing
*Tandem Mass Spectrometry- even small amounts of metabolic
intermediates accumulated in the blood of newborn infants can be
detected
*Liver function tests

21. Management
• Restrict protein intake and supplement with Alpha ketoacids.
• Administration of compounds that bind covalently to non essential
amino acids producing nitrogen containing molecules that are
excreated in the urine
example :phenyl acetate can conjugate with glutamine and glycine
forming Phenylacetatylglutamine and hippurate
• Gene therapy

23. Summary

24. References
• D M Vasudevan
• Harper’s illustrated biochemistry
• Lippincott
• NCBI