What causes hyperammonemia?

Causes of Hyperammonemia

Hyperammonemia is primarily caused by urea cycle disorders, liver diseases, and secondary inhibition of the urea cycle due to congenital metabolic abnormalities, certain medications, and kidney dysfunction. 1

Primary Causes of Hyperammonemia

Urea Cycle Disorders (UCDs)

• Occur in approximately 1 in 35,000 births 1
• Result from congenital deficiencies of enzymes in the urea cycle:
  • N-acetylglutamate synthase (NAGS) deficiency
  • Carbamoyl phosphate synthase I (CPS) deficiency
  • Ornithine transcarbamylase (OTC) deficiency - most common (1 in 56,500 births) 2
  • Argininosuccinate synthetase (ASS) deficiency
  • Argininosuccinate lyase (ASL) deficiency
  • Arginase 1 deficiency

Liver Disease

• Acute liver failure (ALF) 3
• Acute-on-chronic liver failure (ACLF) 3
• Various liver diseases causing impaired ammonia metabolism 2

Organic Acidemias

• Occur in approximately 1 in 21,000 births 1
• Include:
  • Methylmalonic acidemia
  • Propionic acidemia
  • Isovaleric acidemia
  • Multiple carboxylase deficiency
• Lead to mild to moderate hyperammonemia due to competitive inhibition of NAGS 2

Secondary Causes of Hyperammonemia

Renal Dysfunction

• Acute kidney injury 2
• Chronic kidney disease 1
• Impaired excretion of ammonia and urea 2

Medication-Induced

• Valproic acid - inhibits the urea cycle 2, 4
• 5-Fluorouracil (5-FU) 4

Gastrointestinal Causes

• Short bowel syndrome, especially with jejunostomy - inability to manufacture adequate citrulline to detoxify ammonia 1
• Portal blood bypassing the liver (portosystemic shunts) 5

Other Causes

• Hematologic malignancies 4
• Transient hyperammonemia of the newborn - occurs in preterm neonates 1
• Fatty acid oxidation defects 6
• Excessive protein intake or catabolism 5
• Excessive exercise (deamination of AMP in skeletal muscle) 2

Diagnostic Thresholds for Hyperammonemia

• Normal ammonia levels: ≤35 µmol/L (<60 µg/dL) 2, 1
• Hyperammonemia is defined as:

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

  • ≥50 µmol/L (85 µg/dL) in term infants, children, and adolescents 2, 1
• Levels >200 µmol/L (341 µg/dL) are associated with poor neurological outcomes 2, 1

Clinical Implications

Hyperammonemia can result in moderate to severe neurological impairment and cerebral edema 2. Ammonia is neurotoxic and readily crosses the blood-brain barrier 5. In liver failure patients, increased serum ammonia is associated with worse neurological outcomes, including high-grade hepatic encephalopathy, cerebral edema, and intracranial hypertension 3.

Management Considerations

• Protein restriction to reduce nitrogen load 1
• Nitrogen scavengers (sodium phenylacetate and sodium benzoate) that provide alternative pathways for nitrogen excretion 1, 7
• Specific amino acid supplementation based on the underlying disorder 1
• Continuous kidney replacement therapy (CKRT) for severe cases regardless of cause 1
• Arginine supplementation for short bowel syndrome with hyperammonemia 1
• Discontinuation of offending medications (e.g., valproic acid, 5-FU) 4

Early identification and prompt treatment of hyperammonemia is crucial to prevent permanent neurological damage or death, particularly in cases of inherited metabolic disorders presenting in previously healthy individuals 5.