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

From the Guidelines

Elevated ammonia levels, or hyperammonemia, are primarily caused by an excessive accumulation of ammonia in the blood, which can result from various factors including inborn errors of metabolism, liver dysfunction, and certain medications. The causes of hyperammonemia can be categorized into several key areas, including:

• Inborn errors of metabolism, such as urea cycle disorders (UCDs) and organic acidaemias, which can lead to a build-up of ammonia due to enzymatic defects or deficiencies 1.
• Liver dysfunction, where damaged hepatocytes cannot effectively process ammonia, as seen in liver cirrhosis, acute liver failure, and hepatitis.
• Certain medications, such as valproic acid, which can inhibit enzymes involved in ammonia detoxification and lead to hyperammonemia 1.
• Other factors, including gastrointestinal bleeding, excessive protein intake, Reye's syndrome, portosystemic shunts, and severe infections, which can all contribute to elevated ammonia levels. It is essential to identify and address the underlying cause of hyperammonemia to provide effective treatment and reduce the risk of neurological impairment and cerebral edema 1. Key considerations in the management of hyperammonemia include:
• Prompt diagnosis and treatment to prevent long-term neurological damage
• Identification and management of underlying causes, such as liver disease or inborn errors of metabolism
• Use of medications like lactulose or rifaximin to decrease intestinal ammonia production and absorption
• Monitoring of blood ammonia levels to guide treatment and prevent complications 1.

From the FDA Drug Label

Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Hyperammonemia should also be considered in patients who present with hypothermia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone

The causes of elevated ammonia levels (hyperammonemia) include:

• Valproate therapy: Hyperammonemia has been reported in association with valproate therapy, even with normal liver function tests 2
• Concomitant topiramate use: Concomitant administration of topiramate and valproic acid can cause hyperammonemia with or without encephalopathy 2
• Inborn errors of metabolism: Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy 2
• Hypothermia: Hyperammonemia should be considered in patients who present with hypothermia 2
• Unexplained lethargy and vomiting or changes in mental status: Hyperammonemic encephalopathy should be considered in patients who develop unexplained lethargy and vomiting or changes in mental status 2

From the Research

Causes of Elevated Ammonia Levels

Elevated ammonia levels, also known as hyperammonemia, can be caused by various factors. Some of the possible causes include:

• Urea cycle disorders, which are metabolic disorders that affect the body's ability to remove waste nitrogen [(3,4)]
• Valproic acid exposure, which can cause hyperammonemic encephalopathy even in people with normal liver function [(5,6)]
• Liver failure, which can lead to increased serum ammonia levels and worsen neurological outcomes 7
• Certain medications, such as sodium benzoate and sodium phenylacetate, which can be toxic if given in inappropriate doses 3
• Stress-related events, such as prolonged nausea and vomiting, which can trigger increased ammonia levels in people with urea cycle disorders 4

Specific Conditions Associated with Hyperammonemia

Some specific conditions that can cause elevated ammonia levels include:

• Acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) 7
• Urea cycle disorders, such as partial enzyme deficiency 4
• Valproic acid-induced hyperammonemic encephalopathy [(5,6)]
• Hyperammonemia associated with intravenous sodium benzoate and sodium phenylacetate toxicity 3

Importance of Early Detection and Treatment

Early detection and treatment of hyperammonemia are crucial to prevent permanent neurological injury or death [(5,4,7)]. Treatment options may include hemodialysis, administration of scavenging agents, and laxatives [(5,4,7)].