What are the causes of hyperammonemia?

Causes of Hyperammonemia

Hyperammonemia results from either primary defects in the urea cycle enzymes or secondary conditions that impair ammonia detoxification, with urea cycle disorders being the most common primary cause and valproic acid, organic acidemias, and liver/kidney disease being the most frequent secondary causes. 1, 2

Primary Causes: Urea Cycle Disorders (UCDs)

Congenital enzyme deficiencies directly affecting the six enzymes in the urea cycle lead to ammonia accumulation 1, 3:

• N-acetylglutamate synthase (NAGS) deficiency 1
• Carbamoyl phosphate synthase I (CPS) deficiency 1, 3
• Ornithine transcarbamylase (OTC) deficiency - the most common UCD with an incidence of 1 in 56,500 births 1
• Argininosuccinate synthetase (ASS) deficiency 1, 3
• Argininosuccinate lyase (ASL) deficiency 1, 3
• Arginase 1 (ARG) deficiency 1, 3

Transport defects of dibasic amino acids can also cause primary hyperammonemia 4.

Clinical Presentation Patterns by Age

Neonatal-onset (complete enzyme deficiencies):

• Lethargy, poor feeding, and vomiting typically appear within the first few days after feeding begins 1
• Progression to hypotonia, hyperventilation with respiratory alkalosis, hypothermia, anorexia, seizures, neurologic posturing, and coma if untreated 1, 5
• Severe hyperammonemia (≥600 μg/dL or 360 μmol/L) at onset is common 5

Late-onset (partial enzyme deficiencies):

• Failure to thrive, irritability, episodic vomiting triggered by illness or increased protein intake 1
• Ataxia, intellectual disabilities, learning disabilities, delusion, psychosis 1
• Migraine-like headaches and low protein tolerance may be subtle early indicators 1
• Can manifest in childhood, adolescence, or even adulthood when triggered by metabolic stressors 1, 6

Secondary Causes

Organic acidemias (occur in approximately 1 in 21,000 births) 1, 7:

• Methylmalonic acidemia 1, 2
• Propionic acidemia 2
• Isovaleric acidemia 1
• Multiple carboxylase deficiency 1

Drug-induced hyperammonemia:

• Valproic acid (Depakene) inhibits the urea cycle and can cause hyperammonemia even with normal liver function tests 1, 8
• In patients on valproate who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and ammonia level measured 8
• Asymptomatic elevations of ammonia require close monitoring; if elevation persists, discontinuation of valproate should be considered 8

Concomitant topiramate and valproate use:

• This combination is associated with hyperammonemia with or without encephalopathy, even in patients who tolerated either drug alone 8
• Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity are at increased risk 8
• Hypothermia can be a manifestation of this drug interaction 8

Organ dysfunction:

• Acute kidney injury impairs ammonia excretion 1
• Liver disease compromises urea cycle function 2, 9

Defects in mitochondrial fatty acid β-oxidation 7, 4

Transient hyperammonemia of the newborn - probably not genetically determined 4

Physiological Mechanisms of Ammonia Production

Ammonia is produced through 1:

• Amino acid catabolism
• Activity of glutamine dehydrogenase in liver, kidney, pancreas, and brain
• Deamination of AMP during exercise
• Bacterial splitting of urea in the intestines

Normal ammonia processing involves the urea cycle in hepatocytes, conversion to urea for urinary excretion, and conversion to glutamine, which is partially excreted by the kidneys 1.

Diagnostic Thresholds and Clinical Significance

Normal blood ammonia concentrations:

• Adults: ≤35 μmol/L (≤60 μg/dL) 1, 2, 9
• Neonates (1-7 days): ≤110 μmol/L (≤154 μg/dL) 9
• Infants (8-14 days): <90 μmol/L (≤126 μg/dL) 9
• 15 days to adulthood: 16-53 μmol/L (22-74 μg/dL) 9

Hyperammonemia is defined as:

• 100 μmol/L (170 μg/dL) in neonates 1, 2, 9

• ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 2, 9

Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 2, 9

Severe hyperammonemia (>400 μmol/L or 681 μg/dL) may require kidney replacement therapy in pediatric patients 9

Critical Clinical Recognition Points

Respiratory alkalosis is an important early clue that distinguishes hyperammonemia from other causes of encephalopathy 1.

Suspect hyperammonemia in patients with:

• Unexplained neurological symptoms 1
• Respiratory alkalosis 1
• Ataxia, seizures, or coma 1
• Elevated ammonia levels >100 μmol/L with family history of liver disease or neurological disorders 9

Do not wait for seizures, coma, or hypotonia to measure ammonia - these represent advanced manifestations, not early signs 1.

Pathophysiology of Neurotoxicity

• Ammonia crosses the blood-brain barrier in its non-ionized form and is metabolized to glutamine by astrocytes 1, 2, 5
• This causes increased extracellular potassium and intracellular osmolality, leading to cerebral edema 1, 2
• High levels of extracellular potassium and glutamate released by astrocytes cause neuronal damage 2
• Release of inflammatory cytokines contributes to structural brain damage 1, 2

Prognostic Factors

The duration of hyperammonemic coma is the most important prognostic factor, not the rate of ammonia clearance 1:

• Hyperammonemic coma lasting more than 3 days is associated with poor neurological outcomes 1
• Duration of coma inversely correlates with IQ at 12 months after recovery 1
• Plasma ammonia level greater than 1,000 μmol/L is associated with poor outcomes 1
• Increased intracranial pressure worsens prognosis 1