What is Hyperammonaemia?
Hyperammonaemia is the excessive accumulation of ammonia in the blood that causes moderate to severe neurological impairment and cerebral oedema, representing a life-threatening medical emergency requiring immediate recognition and treatment. 1
Definition and Diagnostic Thresholds
Hyperammonaemia is formally defined as:
- >100 µmol/l (170 µg/dl) in neonates
- ≥50 µmol/l (85 µg/dl) in term infants, children and adolescents 1
Normal blood ammonia concentrations are ≤35 µmol/l (<60 µg/dl), while levels >200 µmol/l (341 µg/dl) are associated with poor neurological outcomes 1. Individual laboratory reference intervals vary with some age dependency, as premature neonates naturally have higher levels 1.
Pathophysiology and Neurotoxicity
Ammonia is continuously produced through:
- Amino acid catabolism
- Glutamine dehydrogenase activity in liver, kidney, pancreas, and brain
- Deamination of AMP during skeletal muscle exercise 1
Most ammonia enters the hepatic urea cycle, is excreted as urea in urine, or is converted to glutamine for safe transport and eventual renal excretion 1.
When ammonia accumulates in the brain, it triggers a cascade of neurotoxic events:
- Increased extracellular potassium levels
- Metabolism of ammonia to glutamine by astrocytes
- Increased intracellular osmolality leading to cerebral oedema
- Release of inflammatory cytokines
- Neuronal damage from high extracellular potassium and glutamate 1
Elevated glutamine (the end product of ammonia detoxification) is a key factor in both hepatic encephalopathy and ammonia-related neurotoxicity 1.
Etiologies
Primary Causes (Direct Urea Cycle Defects)
Congenital deficiency of any of the six urea cycle enzymes:
- N-acetylglutamate synthase (NAGS)
- Carbamoyl phosphate synthase I (CPS1)
- Ornithine transcarbamylase (OTC) - most common, occurring in 1 in 56,500 births
- Argininosuccinate synthetase (ASS)
- Argininosuccinate lyase (ASL)
- Arginase 1 (ARG1)
Urea cycle disorders occur in ~1 in 35,000 births 1.
Secondary Causes (Indirect Urea Cycle Inhibition)
- Organic acidaemias (methylmalonic acidaemia, propionic acidaemia, isovaleric acidaemia, multiple carboxylase deficiency) - occur in ~1 in 21,000 births and cause mild to moderate hyperammonaemia through competitive inhibition of NAGS 1
- Drug exposure (particularly valproic acid) 1
- Liver diseases - impaired metabolism 1
- Acute kidney injury - impaired excretion 1
Clinical Presentation
Early Symptoms
- Lethargy
- Loss of appetite
- Vomiting 1
Progressive Symptoms (as ammonia rises)
- Hyperventilation with respiratory alkalosis
- Hypotonia
- Ataxia
- Disorientation
- Seizures
- If untreated: coma and death 1
Age-Specific Presentations
Early-onset (neonates): Presents within the first few days of life after feeding begins, when maternal placental transport is no longer available to eliminate ammonia 1.
Late-onset (children, adolescents, adults): Results from partial or mild enzyme deficiency exacerbated by stressors. Presents with failure to thrive, irritability, seizures, vomiting, ataxia, and intellectual disabilities 1.
Transient hyperammonaemia of the newborn: Occurs in preterm neonates, characterized by absence of organic acidurias and normal urea cycle enzyme activity. Usually resolves completely without treatment 1.
Prognostic Factors
The two critical determinants of neurological damage are:
- Duration of hyperammonaemic coma (>3 days is adverse)
- Peak plasma ammonia levels (>1,000 μmol/l [1,703 μg/dl] is adverse) 1
The duration of coma inversely correlates with IQ at 12 months post-recovery, and brain CT abnormalities correlate with coma duration 1. Prompt identification and treatment have considerably improved neonatal survival 1, though irreversible brain damage remains a significant risk without early intervention.
Clinical Importance
Hyperammonaemia represents a medical emergency where any delay in recognition and treatment may have deleterious consequences 2. In any unexplained change in consciousness or encephalopathy, hyperammonaemia must be excluded as rapidly as possible 2. The condition is particularly challenging in paediatric populations due to non-specific clinical symptoms and age-specific aetiologies 1.