Hyperammonaemia Flashcards
Desribe the production and metabolism of ammonia?
- Ammonia is produced from deamination of amino acids in the liver, muscle and kidney and by the action of gut bacteria.
- Blood in hepatic portal vein is very high in ammonia (up to 20-fold systemic concentrations). Liver has critical role in metabolism and detoxification of ammonia.
- In the liver ammonia is converted to urea, via the urea cycle resulting in subsequent excretion by the kidneys.
How does pH affect amonia?
- At physiological pH, 95% ammonia is in the ammonium ion form (NH4+) which is less permeable to cell membranes.
- When pH rises, equilibrium shifts in favour of ammonia (NH3), entry into cells and toxicity is enhanced.
What are enzymes involved in the urea cycle?
- Carbamoyl phosphate synthetase
- Ornithine transcarbamoylase
- Argininosuccinate synthetase
- Argininosuccinate lyase
- Arginase
- N-acetylglutamate synthetase
How is Cabomoyl Phosphate formed?
Carbamoyl phosphate is formed from bicarbonate and ammonia. It can be converted to either Citrulline or Orotic acid.
- Orotic Acid is a Pyrimidine precursor
- Citrulline be formed from ornithine and carbamoyl phosphate with the influence of ornithine transcarbomoylase. Citrulline can leave mitochondria to form ornithine which can re-enter the mitochondria to be substrate for OTC.
What do changes in Orotic Acid tell us?
Orotic acid is an extra marker for lesions in the point of entry.
- If it isn’t increased, there is hyperammonamenia and there is no increase in the rest of the amino acids within the circle then its most likely N-acetyl Glutamate and Carbomoyl phosphate affected. NGS is used to investigate.
- Orotic acids is particularly important in OTC disorders and in cases where Carbamoyl Phosphate is affected as it isn’t routinely measured.
When are NAGS disorders suspected?
NAGS and Carbomyl Phosphate disorder suspected when:
- Hyperammanaemia where none of the things within the circle and orotic acid isn’t increased.
Next-gen sequencing should be used for NAGS disorders
What are reference ranges for Plasma Ammonia?
- Premature Neonate: < 150 µmol/L
- Term Neonate: < 100 µmol/L
- Infant/ Child: < 40 µmol/L
How can ammonia be toxic?
- Ammonia increases the transport of tryptophan across the blood-brain barrier. This leads to an increased production and release of serotonin.
- Ammonia also increases synthesis of glutamate and increases intracellular osmolality leading to brain swelling
- Ammonia induces many other electrophysiological, vascular and biochemical changes in experimental systems
- Unknown which factors are most harmful in man
What are causes of Hyperamonaemia?
- Artefactual increases
- Transient Hyperammonaemia of the Newborn
What are causes of Arterfactual increases in Ammonia?
- Poor specimen quality/ haemolysis
- Difficult venepuncture
- Skin contamination
- Contaminated sample tube
- Delayed analysis
What should be done in samples where there is delayed analysis?
- But beware of rejecting samples, unlikely for factitious ammonia to be confused with serious hyperammonaemia.
- Ammonias greater than 350 may constitute a medical emergency
What are features of Transient Hyperammonaemia of the Newborn?
- Life-threatening illness presenting in first 48 hours of life
- More likely to occur in pre-term baby – usually as respiratory distress within 24 hours of birth
- Outcome good if treated promptly and aggressively
- Presentation may be indistinguishable from inherited metabolic diseases.
How do defects of the urea cucle cause hyperammonaemia?
- The urea cycle is the final common pathway for the excretion of waste nitrogen.
- Plasma ammonia can be raised as a result of metabolic blocks in the urea-cycle.
- Degree of elevation depends on enzyme involved and its residual activity, protein intake and rate of endogenous protein catabolism (particularly if increased because of infection, fever or other metabolic stresses)
What is the genetic factos in Urea Cycle defects?
- Most common disorder is OTC deficiency (prevalence approx. 1 in 40,000) X-linked.
- All other conditions have autosomal recessive inheritance.
What are some examples of rare urea cycle disorders?
- HHH syndrome (hyperammonaemia, hyperornithinaemia, homocitrullinaemia): Defect of ornithine carrier that imports ornithine into mitochondrion. Reduces flux into urea cycle
- Citrin Deficiency (Citrullinaemia Type II): Citrin is a mitochondrial aspartate-glutamate carrier – both of which are key components in the urea cycle.
- Lysinuric Protein Intolerance: Dibasic amino acid transport defect. Decreased uptake of ornithine, lysine, arginine from gut and increased losses from renal tubule. Reduces metabolite availability for urea cycle
- Carbonic anhydrase deficiency, CA-VA: Mitochondrial enzyme that enables synthesis of bicarbonate as substrate for Carbamoyl phosphate synthetase (CPS). CAVA also supplies HCO3 to three other mitochondrial enzymes, pyruvate carboxylase (gluconeogenesis), propionyl carboxylase and 3methyl crotonyl carboxylase (BCAA catabolism). Hence lactataemia and ketonaemia and hypoglycaemia