What causes elevated ammonia levels?

Causes of Elevated Ammonia Levels

Elevated ammonia levels are primarily caused by urea cycle disorders, liver disease, certain medications (particularly valproic acid), and organic acidemias, all of which impair the body's ability to process and eliminate ammonia effectively. 1

Primary Causes

Congenital Urea Cycle Disorders (UCDs)

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

Liver Disease

• Cirrhosis and acute liver failure significantly impair ammonia detoxification 2
• Liver dysfunction leads to accumulation of ammonia, which is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, and oxidative stress 2

Secondary Causes

Medications

• Valproic acid (Depakene) can inhibit the urea cycle and lead to hyperammonemia 1, 3
• The FDA label for valproic acid specifically warns about hyperammonemia and hyperammonemic encephalopathy as potential adverse reactions 3

Organic Acidemias

• These occur in approximately 1 in 21,000 births and include:
  • Methylmalonic acidemia
  • Isovaleric acidemia
  • Multiple carboxylase deficiency 1

Renal Dysfunction

• Acute kidney injury impairs ammonia excretion 1

Other Causes

• Excessive protein intake can increase blood ammonia levels, especially in individuals with compromised liver function 4
• Bacterial splitting of urea in the intestines contributes to ammonia production 1

Physiological Mechanisms of Ammonia Production

• Normal 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

• Normal ammonia processing involves:

  • The urea cycle in hepatocytes
  • Conversion to urea for urinary excretion
  • Conversion to glutamine, partially excreted by kidneys 1

Clinical Significance

• Normal blood ammonia concentrations are ≤35 μmol/L (≤60 μg/dL) 1, 5
• 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, 5
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 1, 5
• Ammonia is neurotoxic and causes damage to the central nervous system, particularly affecting astrocytes 6

Diagnostic Considerations

• Suspect hyperammonemia in patients with:
  • Unexplained neurological symptoms
  • Respiratory alkalosis
  • Ataxia
  • Seizures
  • Coma 1
• Additional neurological manifestations include:
  • Tremors
  • Dysarthria (speech difficulty)
  • Confusion and lethargy
  • Hypotonia
  • Migraine-like headache
  • Learning disabilities and neurodevelopmental delay 5

Clinical Pearls and Pitfalls

• Ammonia levels should be measured promptly in neonates with deteriorating feeding, drowsiness, and tachypnea after an initial well period 7
• Ammonia levels above 200 μmol/L usually indicate inherited metabolic diseases 7
• Even mild hyperammonemia can cause neurological damage; levels above 90 μM can decrease viability of neuronal cells by 14% 4
• Patients with liver disease may benefit from decreasing protein consumption to reduce blood ammonia levels 4
• Carriers of disease-causing CPS1 alleles may have triple the normal blood ammonia levels and might benefit from monitoring ammonia levels and limiting protein intake 4