What are the causes of hyperammonemia?

Causes of Elevated Ammonia

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

Urea Cycle Disorders (UCDs)

• Congenital enzyme deficiencies in the urea cycle (incidence ~1 in 35,000 births) 1:
  • N-acetylglutamate synthase (NAGS) deficiency
  • Carbamoyl phosphate synthase I (CPS) deficiency
  • Ornithine transcarbamylase (OTC) deficiency (most common, 1 in 56,500 births)
  • Argininosuccinate synthetase (ASS) deficiency
  • Argininosuccinate lyase (ASL) deficiency
  • Arginase 1 deficiency

Liver Disease

• Acute liver failure
• Chronic liver disease/cirrhosis
• Portal hypertension with portosystemic shunting 2

Secondary Causes

Metabolic Disorders

• Organic acidemias (incidence ~1 in 21,000 births) 1:
  • Methylmalonic acidemia
  • Propionic acidemia
  • Isovaleric acidemia
  • Multiple carboxylase deficiency

Medications

• Valproic acid 1, 3
• 5-Fluorouracil (5-FU) 3

Gastrointestinal Causes

• Upper gastrointestinal bleeding in cirrhotic patients 2
  • Hemoglobin breakdown leads to protein of low biological value (lacks isoleucine)
  • Causes impaired protein synthesis and increased ammoniagenesis

Renal Causes

• Acute kidney injury
• Chronic kidney disease 1
• Renal ammoniagenesis (particularly important after GI bleeding) 2

Short Bowel Syndrome

• In patients with short bowel, especially with jejunostomy 1
  • Due to inability to manufacture adequate citrulline to detoxify ammonia via the urea cycle
  • Worsens with concomitant renal impairment

Intense Skeletal Muscle Activity

• Extreme muscle exertion can cause transient hyperammonemia 4
  • Due to increased ammonia production from deamination of AMP during exercise
  • Can occur even with normal liver function

Other Causes

• D(2) lactic acidosis (in patients with short bowel and preserved colon) 1
• Hematologic malignancies 3
• Transient hyperammonemia of the newborn 1
  • Occurs in preterm neonates
  • Characterized by absence of organic acidurias and normal urea cycle enzyme activity
  • Usually resolves without treatment

Clinical Manifestations

Hyperammonemia presents with progressive neurological symptoms:

• Early: Lethargy, loss of appetite, vomiting
• Progressive: Hyperventilation (respiratory alkalosis), hypotonia, ataxia, disorientation
• Severe: Seizures, coma, and potentially death 1

Diagnostic Thresholds

• Normal ammonia: ≤35 µmol/L (<60 µg/dL)
• Hyperammonemia defined as:

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

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

Important Considerations in Diagnosis

• Preanalytical factors can affect ammonia measurements 5

  • Proper sample collection and handling is critical
  • False elevations can occur with improper technique

• In patients with normal liver function but elevated ammonia, consider:

  • Inborn errors of metabolism
  • Medication effects
  • Extreme physical exertion
  • Short bowel syndrome

Treatment Approach

Treatment depends on the underlying cause but generally includes:

1. For UCDs and organic acidemias:

   • Protein restriction
   • Nitrogen scavengers
   • Specific amino acid supplementation 1

2. For short bowel syndrome with hyperammonemia:

   • Arginine supplementation to correct the deficiency 1

3. For medication-induced hyperammonemia:

   • Discontinuation of the offending agent 3

4. For severe cases regardless of cause:

   • Extracorporeal therapies may be required 5
   • Continuous kidney replacement therapy (CKRT) 1

Early recognition and prompt treatment are essential to prevent permanent neurological damage, as coma duration, ammonia peak level, and hyperammonemia duration are the main risk factors for poor outcomes 5.