What are the causes of hyperammonemia (elevated ammonia levels)?

From the Guidelines

Hyperammonemia is primarily caused by urea cycle disorders, liver disease, and certain medications, which lead to the accumulation of toxic levels of ammonia in the blood. The condition can result from primary or secondary deficiencies of the urea cycle enzymes, including N-acetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase 1 (ARG1) 1. Other causes of hyperammonemia include organic acidemias, such as methylmalonic acidemia, propionic acidemia, and isovaleric acidemia, as well as exposure to certain drugs like valproic acid 1. Paediatric patients with liver diseases or acute kidney injury are also susceptible to hyperammonemia due to impaired metabolism or excretion of urea 1.

Causes of Hyperammonemia

• Urea cycle disorders
• Liver disease
• Certain medications (e.g., valproic acid)
• Organic acidemias (e.g., methylmalonic acidemia, propionic acidemia, isovaleric acidemia)
• Acute kidney injury

Key Points

• Hyperammonemia can cause neurological symptoms ranging from mild confusion to coma
• Treatment focuses on reducing ammonia levels through medications and dietary protein restriction
• Hemodialysis may be necessary for severe cases unresponsive to medical therapy
• Regular monitoring of ammonia levels, neurological status, and electrolytes is essential during treatment
• The underlying cause of hyperammonemia must be identified and addressed to prevent further complications 1.

From the FDA Drug Label

Urea cycle disorders can result from decreased activity of any of the following enzymes: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG)

The causes of hyperammonemia (elevated ammonia levels) include:

• Urea cycle disorders due to decreased activity of certain enzymes, such as:
  • N-acetylglutamate synthetase (NAGS)
  • Carbamyl phosphate synthetase (CPS)
  • Argininosuccinate synthetase (ASS)
  • Ornithine transcarbamylase (OTC)
  • Argininosuccinate lyase (ASL)
  • Arginase (ARG) 2 2

From the Research

Causes of Hyperammonemia

The causes of hyperammonemia can be attributed to various factors, including:

• Inherited enzymatic defects in the urea cycle or related metabolic pathways 3
• Urea cycle disorders, such as deficiencies of urea cycle enzymes, transport defects of dibasic amino acids, organic acidemias, and defects in beta-oxidation of fatty acids 3
• Acquired conditions, such as liver failure and acute kidney injury (AKI) combined with a large intra-abdominal haematoma producing nitrogen waste products 4
• Stress-related events that trigger increased ammonia levels, such as prolonged nausea and vomiting, or recent surgical procedures 5
• Late-onset ornithine carbamoyltransferase deficiency, a rare urea cycle disorder that can cause hyperammonemia in adults 6

Urea Cycle Disorders

Urea cycle disorders are a group of metabolic disorders that can cause hyperammonemia due to:

• Deficiencies of urea cycle enzymes 3, 5
• Partial enzyme deficiency associated with urea cycle disorder, which can lead to ammonia buildup in female carriers with partial activity of any urea cycle enzyme 5
• Ornithine carbamoyltransferase (OTC) deficiency, a urea cycle disorder that can cause the accumulation of ammonia and lead to encephalopathy 6

Other Causes

Other causes of hyperammonemia include:

• Transient hyperammonemia of the newborn, a condition that is probably not genetically determined 3
• Intra-abdominal haematoma producing nitrogen waste products, which can contribute to hyperammonemia in patients with liver failure and AKI 4