What causes hyperammonemia (high ammonia levels)?

Causes of Hyperammonemia

Hyperammonemia is primarily caused by urea cycle disorders, liver disease, certain medications, and metabolic conditions that impair the body's ability to process and excrete ammonia properly.

Primary Causes

Urea Cycle Disorders (UCDs)

• Congenital deficiency of any of the six enzymes in the urea cycle leads to ammonia accumulation 1:
  • N-acetylglutamate synthase (NAGS) deficiency
  • Carbamoyl phosphate synthase I (CPS) deficiency
  • Ornithine transcarbamylase (OTC) deficiency - most common UCD with incidence of 1 in 56,500 births 1
  • Argininosuccinate synthetase (ASS) deficiency
  • Argininosuccinate lyase (ASL) deficiency
  • Arginase 1 deficiency

Liver Disease

• Acute or chronic liver disease impairs ammonia metabolism in hepatocytes 1, 2
• Cirrhosis, acute liver failure, and acute-on-chronic liver failure all lead to hyperammonemia 2
• Portal hypertension causes blood to bypass the liver (portosystemic shunting), preventing ammonia detoxification 3

Secondary Causes

Metabolic Disorders

• Organic acidemias occur in approximately 1 in 21,000 births 1:
  • Methylmalonic acidemia
  • Propionic acidemia
  • Isovaleric acidemia
  • Multiple carboxylase deficiency 1, 4
• Fatty acid oxidation defects impair ammonia metabolism 5

Medication-Induced

• Valproic acid (Depakene) - commonly used anticonvulsant that can inhibit the urea cycle 1, 4, 6
• Haloperidol can potentially exacerbate hyperammonemia in susceptible individuals 6

Other Causes

• Acute kidney injury - impairs ammonia excretion 1, 4
• Excessive protein intake or catabolism - increases ammonia production 6, 7
• Transient hyperammonemia of the newborn - typically resolves without treatment 1
• Pregnancy-related complications - hyperemesis gravidarum can trigger hyperammonemia in those with underlying UCDs 7
• Intense exercise - deamination of AMP during skeletal muscle exertion 1

Physiological Mechanisms

• Ammonia is produced through:

  • 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 1, 2

• Normal ammonia processing:

  • Most ammonia enters the urea cycle in hepatocytes
  • Converted to urea for urinary excretion
  • Some converted to glutamine, partially excreted by kidneys 1

Clinical Significance

• Normal blood ammonia concentrations are ≤35 μmol/L (<60 μg/dL) 1, 4
• Hyperammonemia is defined as:

  • 100 μmol/L (170 μg/dL) in neonates

  • ≥50 μmol/L (85 μg/dL) in term infants, children, and adults 1, 4
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 4

Diagnostic Considerations

• Suspect hyperammonemia in patients with:
  • Unexplained neurological symptoms (lethargy, vomiting, confusion)
  • Respiratory alkalosis
  • Ataxia, seizures, or coma 1, 4
• Atypical presentation of acute liver injury with mild elevation of aminotransferases but severe hyperammonemia should prompt investigation for urea cycle disorders 7
• Early diagnosis and treatment are critical to prevent irreversible neurological damage 6, 8

Treatment Approaches

• Acute management of severe hyperammonemia may require:
  • Protein restriction
  • Nitrogen scavenger medications
  • Renal replacement therapy in severe cases 6, 8
• Long-term management of UCDs includes:
  • Dietary protein restriction
  • Essential amino acid supplementation
  • Medications like sodium phenylbutyrate 6