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

From the Guidelines

Hyperammonemia is primarily caused by impaired metabolism and excretion processes, such as urea cycle disorders, liver disease, and kidney injury, which can lead to an accumulation of ammonia in the blood, resulting in neurological symptoms and potentially life-threatening complications. The causes of hyperammonemia can be categorized into several key areas, including:

• Urea cycle disorders, such as carbamoyl phosphate synthase I (CPS) deficiency, ornithine transcarbamylase (OTC) deficiency, and argininosuccinate synthase (Ass) deficiency 1
• Liver disease, such as acute liver failure or cirrhosis, which can impair the liver's ability to metabolize ammonia 1
• Kidney injury, such as acute kidney injury or chronic kidney disease, which can impair the kidneys' ability to excrete ammonia 1
• Other causes, such as certain medications, infections, and metabolic disorders, which can also contribute to the development of hyperammonemia 1

The symptoms of hyperammonemia can vary depending on the age of the patient and the underlying cause, but common symptoms include:

• Confusion and altered mental status
• Seizures
• Cerebral edema (brain swelling)
• Coma in severe cases These symptoms occur because excess ammonia in the blood crosses the blood-brain barrier and interferes with neurotransmitter function, leading to osmotic stress and swelling of astrocytes, which contributes to cerebral edema 1

Treatment of hyperammonemia focuses on reducing ammonia levels through:

1. Stopping protein intake temporarily
2. Administering medications, such as sodium benzoate and sodium phenylacetate, to trap ammonia in the gut
3. Giving medications, such as l-arginine and l-carnitine, to support ammonia metabolism
4. In severe cases, starting hemodialysis or continuous kidney replacement therapy to rapidly remove ammonia from the blood Identifying and addressing the underlying cause of hyperammonemia is crucial for long-term management, and patients should be closely monitored in a hospital setting until ammonia levels normalize and symptoms improve 1

From the Research

Causes of Hyperammonemia

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

• Liver dysfunction, such as cirrhosis or portosystemic shunting 2, 3
• Inborn metabolic errors, such as:
  • Urea cycle disorders (UCDs) 4, 5, 6
  • Fatty acid oxidation defects 4
  • Pyruvate metabolism disorders 4
• Hemato-oncological disorders 4
• Urea splitting bacterial infections 4
• Non-cirrhotic hyperammonemia of unknown etiology 4
• Medications and environmental causes 6
• Ornithine transcarbamylase (OTC) deficiency, a type of UCD 5
• Citrin deficiency, a type of UCD, although this was ruled out in one case 4

Non-Cirrhotic Causes

Non-cirrhotic causes of hyperammonemia are less well-known, but can include:

• Inborn metabolic errors, such as UCDs and fatty acid oxidation defects 4, 5, 3
• Hemato-oncological disorders 4
• Urea splitting bacterial infections 4
• Portosystemic shunts 3

Diagnosis and Investigation

Diagnosis and investigation of hyperammonemia require a high index of suspicion, especially in cases of non-cirrhotic hyperammonemia 5, 3. Measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status 3. A framework for investigating the acute non-cirrhotic causes of hyperammonaemia can assist both chemical pathologists and clinicians managing these often challenging cases 3.