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

From the Guidelines

Hyperammonemia is primarily caused by conditions that either increase ammonia production or decrease ammonia elimination from the body, with the most common causes being liver dysfunction and genetic disorders of the urea cycle, such as ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase deficiency, as reported in a 2020 study 1. The causes of hyperammonemia can be categorized into two main groups:

• Conditions that increase ammonia production, such as
  • Gastrointestinal bleeding, which increases ammonia levels as blood proteins are broken down by gut bacteria
  • Excessive protein intake, particularly in patients with compromised liver function, which can overwhelm the body's ammonia processing capacity
  • Urinary tract infections with urease-producing bacteria like Proteus, which can convert urea to ammonia
  • Severe muscle exertion or trauma, which can release ammonia from muscle breakdown
• Conditions that decrease ammonia elimination from the body, such as
  • Liver dysfunction, particularly cirrhosis, acute liver failure, and hepatitis, as the liver is primarily responsible for converting ammonia to urea for excretion
  • Genetic disorders of the urea cycle, which prevent proper ammonia metabolism and can cause severe hyperammonemia, especially in newborns
  • Certain medications like valproic acid, carbamazepine, and some chemotherapeutic agents, which can induce hyperammonemia by interfering with ammonia metabolism
  • Portosystemic shunts, whether congenital or acquired, which allow blood to bypass the liver, preventing ammonia detoxification. According to a 2020 study, hyperammonemia can also be caused by secondary inhibition of the urea cycle, which occurs in the context of other congenital metabolic abnormalities, such as organic acidemias, and following exposure to certain drugs 1. A 2014 study also highlights the importance of considering liver transplantation as a treatment option for patients with severe urea cycle disorders, as it can serve as an "enzyme replacement" therapy and allow for resumption of a normal diet and elimination of hyperammonemic crises 1.

From the FDA Drug Label

In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. 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 include:

• Inborn errors of metabolism: such as urea cycle disorders due to decreased activity of enzymes like N-acetylglutamate synthetase, carbamyl phosphate synthetase, argininosuccinate synthetase, ornithine transcarbamylase, argininosuccinate lyase, or arginase.
• Reduced hepatic mitochondrial activity: which may increase the risk of hyperammonemia with or without encephalopathy.
• Concomitant use of certain medications: such as valproate and topiramate, which can increase the risk of hyperammonemia 2.

From the Research

Causes of Hyperammonemia

The causes of hyperammonemia can be classified into primary and secondary hyperammonemias, depending on the underlying pathophysiology 3.

• Primary hyperammonemia occurs when the urea cycle is directly affected by a defect of any of the involved enzymes or transporters, such as ornithine transcarbamylase (OTC) deficiency 4, 5, 6, 7.
• Secondary hyperammonemia occurs when the function of the urea cycle is inhibited by toxic metabolites or by substrate deficiencies 3. Other causes of hyperammonemia include:
• Primary hepatic failure 4
• Drug toxicity, such as valproic acid 7
• Infection 4
• Inherited disorders of metabolism, such as OTC deficiency 4, 5, 6, 7
• Exogenic factors, such as gastrointestinal haemorrhage, gastric bypass surgery, starvation, seizures, vigorous exercise, burn injuries, or drugs hampering the elimination of ammonia 6

Underlying Conditions

Hyperammonemia can occur in various underlying conditions, including:

• Ornithine transcarbamylase deficiency (OTC) 4, 5, 6, 7
• Urea cycle disorders 3
• Liver disease 3
• Inborn errors of metabolism 6
• Genetic disorders, such as OTC deficiency 4, 5, 6, 7